Pyrrolo[2,3-d]pyrimidine derivatives, process for producing the same and pharmaceutical preparation comprising the same as active ingredient

ABSTRACT

A pyrrolo[2,3-d]pyrimidine derivative having the general formula [I] ##STR1## wherein R 1 , R 2 , R 3 , R 4 , R 5 , Y and Z have the same definitions as those given in the description, a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutical preparation comprising the same, are provided.

This is a continuation of application No. 08/203,494 filed on Feb. 28,1994, abandoned which is a continuation of application Ser. No.08/024,380, filed on Mar. 1, 1993, now abandoned, which is acontinuation-in-part of application Ser. No. 07/863,168, filed Apr. 3,1992, now abandoned, which is a continuation-in-part of application Ser.No. 07/838,813, filed Mar. 18, 1992, now abandoned.

TECHNICAL FIELD

The present invention relates to a novel pyrrolo[2,3-d]pyrimidinederivative, a process for producing same, and a pharmaceuticalpreparation comprising the derivative, and more particularly, relates toa novel pyrrolo[2,3-d]pyrimidine derivative having independently asubstituted or unsubstituted amino group at the 2- and 4- positions ofthe pyrimidine ring, a pharmaceutically acceptable acid addition saltthereof, a process for producing same, and a pharmaceutical preparationcomprising same as an active ingredient; particularly, a pharmaceuticalpreparation useful for the treatment, i.e., prophylaxis and therapy, ofhypoxemia associated with respiratory diseases.

BACKGROUND ART

Compounds having the pyrrolo[2,3-d]pyrimidine skeleton of the formula:##STR2## are known to have various important pharmacological actions.For example, it is known that antibacterial compounds are substituted byamino groups at both the 2- and 4- positions of the skeleton (see, U.K.Patent 812, 366, and Townsend L. B. et al, J. Med. Chem., Vol. 31,1501(1988), etc.). and that compounds useful as a herbicide andantibiotic have a primary amino group as the amino group (Okuda et al,Nippon Noyaku-gakkaishi, Vol. 6, 9(1981), Pedersen E. B. et al., ChemicaScripta, Vol. 28, 201(1988), etc.), other known antiviral compounds havean amino group at the 2- and 4- positions as well as a sugar residue atthe 7- position of the skeleton (e.g., E.P. Publication No. 57548).

Nevertheless, in particular, pyrrolo[2,3-d]pyrimidine derivatives havingan alkyl or alkenyl group at the 7- position, an amino group substitutedby alkyl or alkenyl group at the 2- position, and a cyclic amino orchain substituted amino group at the 4- position, have not beendescribed in the prior art.

DISCLOSURE OF INVENTION

The present inventors made extensive and intensive research intopyrrolo[2,3-d]pyrimidine derivatives and a process for producing same,and as a result, surprisingly found that, of the compounds not disclosedin the prior art, those of the formula I described below areparticularly, efficacious for the prophylaxis and therapy of hypoxemiaassociated with respiratory diseases. Note, in the treatment ofhypoxemia, to this day it has not been known that a compound can sufficein the light of both the pharmaceutical effect and toxicity there.

Thus, in accordance with the present invention there are provided,pyrrolo[2,3-d]pyrimidine derivatives having the formula I describedbelow, pharmaceutically acceptable acid addition salts thereof, aprocess for producing same, as well as pharmaceutical preparationscontaining same derivatives or salts as an active ingredient: ##STR3##wherein R¹ represents a hydrogen atom, or an unsubstituted orsubstituted alkyl, alkenyl or arylalkyl group;

R² and R³, independently of each other, represent a hydrogen atom, or anunsubstituted or substituted alkyl, alkenly, arylalkyl or alkylcarbonylgroup; or R² and R³ are optionally taken together with the adjacentnitrogen atom to form a mono-cyclic amino group;

R⁴ and R⁵ independently of each other, represent a hydrogen atom,halogen atom, or an unsubstituted or substituted alkyl group;

Y is a linking group bonded to the pyrimidine ring via a nitrogen atomtherein of the formula ##STR4## wherein G represents a hydrogen atom oran alkyl group; Z represents a group bonded to a carbon or nitrogen atomin the linking group, and is a hydrogen atom, an unsubstituted orsubstituted alkyl, alkenyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, alkylcarbonyl, arylcarbonyl heteroarylcarbonyl,arylalkylcarbonyl, heteroarylalkylcarbonyl or heteroalicyclic group; orrepresents a group bonded to a carbon atom in the linking group, and isa carboxyl, hydroxyl; or an unsubstituted or substitutedalkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy,arylalkylcarbonyloxy, heteroarylalkylcarbonyloxy, alkyloxy oralkyloxyiminoalkyl group; or mono- or di-alkylamino, mono- ordi-alkylcarbonylamino, or N-alkyl-N-alkylcarbonylamino group; or Y and Zare taken together. to form morpholino or thio-morpholino group;

each substituent in said substituted group is substituted at a chain orcyclic moiety of the alkyl, alkenyl, aryalkyl, heteroarylalkyl, aryl,heteroaryl, or heteroalicyclic moiety, respectively, and represents anunsubstituted or substituted alkyl, alkyloxy, aryloxy, alkylcarbonyl,alkylcarbonyloxy, heteroalicyclic, hydroxy, mono- or di-alkylamino,amino, nitro, cyano group, or a halogen atom, wherein the substitutedgroup, at a chain or cyclic moiety thereof, has further one or moresubstituents including alkyloxy, hydroxy, amino, nitro, cyano group andhalogen atom, e.g., F, Cl, Br or I;

with a proviso that R² and R³ do not represent a hydrogen atom at thesame time, and that, when R¹ represents hydrogen atom, the combinationswherein one of R² and R³ represents a hydrogen atom and anotherrepresents an alkyl group are excluded.

BEST MODE OF CARRYING OUT THE INVENTION

This invention is disclosed in detail below.

An alkyl moiety of each group, unless defined otherwise, is hereinintended to mean a C₁ -C₁₀ straight or branched chain aliphatichydrocarbon residue, alicyclic hydrocarbon residue orchainaliphatic-alicyclic hydrocarbon residue, and is for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopropyl-methyl and cyclobuthymethyl; preferably a C₁ -C₆lower alkyl group.

The term "alkenyl group" is intended to mean a C₂ -C₆ straight orbranched chain aliphatic hydrocarbon residue containing one double bond,for example, allyl, 1-methylallyl, 2-methylallyl, 2-butenyl,2-methyl-2-butenyl, 3-methyl-2-buteny, 3-butenyl, 2-pentenyl,3-methyl-2-pentenyl, 2-hexenyl, 3-cyclopropylally, 3-cyclopentenyl and3-cyclohexenyl.

The term "aryl group" is intended to mean C₆ -C₁₀ aromatic hydrocarboncyclic groups constructed of a mono-ring or fused ring and examplesthereof include phenyl, 1-naphthyl and 2-naphthyl. The term "heteroarylgroup" is intended to mean 4- to 6-member of unsaturated cyclic groupscontaining 1 to 3 hetero atoms, e.g., N, S, O, which are constructed bya mono-cyclic ring or fused cyclic ring. Examples of the former includepyrrolyl, furyl, thienyl and pyridyl, and those of the latter includeindolyl, benzofuryl, benzothienyl, pyrrolopirimidinyl and carbazolyl.

The term "arylalkyl group", which is constructed of said lower alkylgroup and said aryl group, and containing in total 6 to 20 carbon atoms,for example, benzyl, 1-phenylethyl, 1-methyl-1-phenylethyl,2-phenylethyl, 3-phenylpropyl, cinnamyl, diphenylmethyl (benzhydryl),triphenylmethyl, 1-naphthylmethyl, 1-(1-naphthy)ethyl,1,2,3,4-tetrahydronaphtharen-1-yl.

The term "heteroarylalkyl group", which is constructed of said loweralkyl group and heteroaryl group, for example, is 2-pyrrolylmethyl,2-furfuryl, 2-thienylmethyl, 2-pyridylmethyl, 2-(2-pyrrolyl)ethyl,2-(2-furyl)ethyl and 3-(2-furyl)propyl.

The term "heteroalicyclic group" is intended to mean 4- to 6-member ofsaturated hetero mono-cyclic groups containing 1 to 3 hetero atoms,e.g., N, S, O, and, for example, pyrrolidinyl, tetrahydrofuryl,tetrahydrothiophen-yl, piperidinyl, morpholinyl, thiomorpholinyl andtetrahydropyranyl.

The above-described alkyl, alkenyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl and heteroalicyclic groups may have a substituent in thechain moiety or cyclic moiety thereof, and examples of the substituentinclude an unsubstituted or substituted alkyl, alkyloxy, aryloxy,alkylcarbonyl, alkylcarbonyloxy, heteroalicyclic, hydroxy, mono- ordi-alkylamino, amino, nitro, cyano group, or a halogen atom, wherein thesubstituted group, at a chain or cyclic moiety thereof, has further oneor more substitutents including alkyloxy, hydroxy, amino, nitro, cyanogroup and halogen atom, e.g., F, Cl, Br or I; The groups defined belowalso may have the above-described substituents in the chain portion orcyclic portion thereof.

In the present invention, the term "alkylcarbonyl group", which isconstructed of said lower alkyl and carbonyl group, is intended to meanC₂ -C₇ lower alkylacyl, groups, such as acetyl, propanoyl, butanoyl,2-methylpropanoyl, pentanoyl, 2-methylbutanoyl, 3-methylbutanoyl,pivaloyl, hexanoyl and cyclopropylcarbonyl.

The term "arylcarbonly group", which is constructed of said aryl andcarbonyl group, is intended to mean, for example, benzoyl, toluoyl,naphthoyl.

The term "heteroarylcarbonyl group", which is constructed of saidheteroaryl and carbonyl group, is intended to mean, for example,2-pyrrolecarbonyl, 2-furancarbonyl and 2-thiophenecarbonyl.

The term "arylalkylcarbonyl group", which is constructed of saidarylalkyl and carbonyl group, is intended to mean C₇ -C₁₉arylalkylcarbonyl groups, such as phenylacetyl, 3-phenylpropanoyl,4-phenylbutanoyl, cinnamoyl, diphenylacetyl and naphthylacetyl.

The term "heteroarylalkylcarbonyl group", which is constructed of saidheteroarylalkyl and carbonyl group, is intended to mean, for example,2-pyrrolylacetyl, 2-furylacetyl and 2-thienylacetyl.

The term "alkyloxycarbonyl group", which is a carboxylic acid esterresidue containing said alkyl group, is intended to mean C₂ -C₇ loweralkyloxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropyloxycarbonyl, butoxycarbonyl,tert-butyloxycarbonyl and cyclohexyloxycarbonyl.

The term "alkylcarbonyloxy group" which is constructed of saidalkylcarbonyl and oxy group, is intended to mean C₂ -C₇ loweralkylcarbonyloxy groups, such as acetoxy, propanoyloxy, butanoyloxy,2-methylpropanoyloxy, pentanoyloxy, pivaloyloxy and hexanoyloxy.

The term "arylcarbonyloxy group", which is constructed of saidarylcarbonyl and oxy group, is intended to mean, for example,benzoyloxy, toluoyloxy, naphthoyloxy.

The term "heteroarylcarbonyloxy group", which is constructed of saidheteroarylcarbonyl and oxy group, is intended to mean, for example,2-pyrrolecarbonyloxy, 2-furancarbonyloxy and 2-thiophenecarbonyloxy.

The term "arylalkylcarbonyloxy group", which is constructed of saidarylalkylcarbonyl and oxy group, is intended to mean lowerarylalkylacyloxy groups, such as phenylacetoxy, 3-phenylpropanoyloxy,4-phenylbutanoyloxy and cinnamoyloxy.

The term "heteroarylalkylcarbonyloxy group", which is constructed ofsaid heteroarylalkylcarbonyl and oxy group, is intended to mean, forexample, 2-pyrrolylacetoxy, 2-furylacetoxy and 2-thienylacetoxy.

The term "alkyloxy group", which is constructed of said alkyl and oxygroup, is intended to mean a C₁ -C₆ lower alkyloxy group; such asmethoxy, ethoxy, propoxy, butoxy, isopropyloxy, sec-butyloxy,tert-butyloxy, pentyloxy, cyclopropyloxy, cyclopropylmethyloxy, andcyclohexyloxy.

The term "alkyloxyiminoalkyl group" represents a group that, in thealkylcarbonyl groups, the oxygen atom is replaced with a groupN-O-alkyl, and has the formula: ##STR5## The term "mono- ordi-alkylamino, mono- or di-alkylcarbonylamino orN-alkyl-N-alkylcarbonylamino group", represents amino groups substitutedby one or two substituents selected from the same or different saidlower alkyl or lower alkylcarbonyl group such as, methylamino,ethylamino, propylamino, butylamino, cyclohexylamino, dimethylamino,diethylamino, N-methylbuthylamino, acetylamino, propanoylamino,pivaloylamino, N-methylacetylamino and N-ethytacetylamino group.

The term "halogen atom" is intended to mean a fluorine atom, a chlorineatom, a bromine atom and an iodine atom.

According to the above-described definitions, the R¹ in the generalformula I includes a hydrogen atom, or an unsubstituted or substitutedalkyl group, alkenyl group, arylalkyl group and alkylcarbonyl group.

Suitable specific examples of the alkyl group include methyl, ethyl,propyl, isopropyl, butyl, cyclopropyl, cyclopropylmethyl,trifluoromethyl, methoxymethyl, methoxyethoxymethyl and aminoethyl.Suitable specific examples of the alkenyl group include allyl,2-methylallyl, 2-butenyl, 3-methyl-2-butenyl, 2-fluoroallyl,3-fluoroally, 2-(trifluoromethyl)allyl and 3-butenyl. Suitable specificexamples of the arylalkyl group include benzyl, 4-fluorobenzyl,4-chlorobenzyl, 3-(trifluoromethyl)benzyl, 4-methoxybenzyl,2-phenylethyl, 2-[(2-trifluoromethyl)phenyl]ethyl, triphenylmethyl and(4-methoxyphenyl)diphenylmethyl. Suitable specific examples of thealkylcarbonyl group include acetyl, trifluoroacetyl, propanoyl,2-methylpropanoyl and butanoyl.

The R² and R³ in the general formula I are respectively identical withthe R¹, and suitable examples thereof as well are identical with thoseof R¹. The R² and R³ may be taken together with an adjacent nitrogenatom to form a cyclic amino group. The cyclic amino group is a saturatedfive- to seven-membered ring and may further have at least one cyclichetero atom (for example, N, O or S) in its ring other than theabove-described nitrogen. Suitable specific examples of the cyclic aminogroup include 1-pyrrolidinyl, piperidino, 1-piperazinyl,4-[bis(4-fluorophenyl)methyl]-1-piperazinyl, morpholino, thiomorpholinoand 1-perhydro[1,4]diazepinyl.

The R⁴ and R⁵ in the general formula I each independently represent ahydrogen atom, a halogen atom or an substituted or substituted alkylgroup. Suitable specific examples of the halogen atom include a fluorineatom, a chlorine atom and a bromine atom. Suitable examples of the alkylgroup include methyl, ethyl and trifluoromethyl.

In the general formula I, the Y represents a linking group, which isbonded to the pyrimidine ring via a nitrogen atom therein, of theformula ##STR6## wherein G represents a hydrogen atom or an alkyl group.Suitable specific examples of the same include groups of the formula:##STR7##

In the general formula I, where Z bonds with a carbon atom or nitrogenatom in the linking group, suitable specific examples there of include ahydrogen atom; an alkyl group such as methyl, ethyl, propyl, isopropyl,tert-butyl, isobutyl, cyclohexyl, ethoxyethyl,2-(3,5-dimethoxyphenoxy)ethyl, 1,3-dimethoxy-2-propyl,trans-4-hydroxycyclohexyl, trans -4-methoxycyclohexyl,cis-4-methoxycyclohexyl, trans-4-(2-ethoxy ethoxy)cyclohexyl,dimethyaminoethyl, morpholinoethyl, piperidinoethyl andtetrahydrofurfuryl; an alkenyl group such as allyl, 2-methylallyl,2-butenyl, 3-methyl-2-butenyl, 2-fluoroally, 3-flouroallyl,2-(trifluoromethyl)allyl and 3-butenyl; an arylalkyl group such asbenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 3-(trifluoromethyl)-benzyl,4-methoxybenzyl, 1-phenylethyl, 1-methyl-1-phenylethyl, 2-phenylethyl,2-(4-fluorophenyl)-ethyl, 2-(4-chlorophenyl)ethyl,2-(4-methoxyphenyl)ethyl, 2-[2-(trifluoromethyl)phenyl]-ethyl, cinnamyl,diphenylmethy, bis(4-fluorophenyl)methyl, 1-(1-naphthyl)ethyl,1,2,3,4-tetrahydronaphthalene-1-yl; a heteroarylalkyl group such as2-pyrrolyl-methyl, 2-furfuryl, 2-thienylmethy and 3-(2-furyl)propyl; anaryl group such as phenyl, 4-fluorophenyl, 4-chlorophenyl and4-methoxphenyl; an alkylcarbonyl group such as acetyl, trifluoroacetyl,propanoyl, 2-methylpropanoyl, butanoyl, pivaloyl, andcyclopropylcarbonyl; an arylcarbonyl group such as benzoyl,4-fluorobenzoyl, 4-chlorobenzoyl, 3-methoxybenzoyl, 4-toluoyl and1-naphthoyl; a heteroarylcarbonyl group such as 1-pyrrolocarbonyl,2-furylcarbonyl and 2-thiophenecarbonyl; and an arylalkylcarbonyl groupsuch as phenylacetyl, 4-fluorophenylacetyl, 3-phenylpropanonyl,cinnamoyl and diphenylacetyl; a heteroalicyclic group such as2-pyrrolidnyl, 2-tetrahydrofuryl, piperidino, 4-piperidinyl, morpholino,2-morpholinyl, 2-tetrahydropyranyl and 4-tetrahydropyranyl.

Where Z bonds with a carbon atom in the linking group, suitable otherspecific examples include a carboxyl group; hydoxyl group;alkyloxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl and tert-butyloxycarbonyl; alkylcarbonyloxy groupsuch as acetyloxy, propanoyloxy, 2-methylpropanoyloxy and pivaloyloxy;arylcarbonyloxy group such as benzoyloxy, 4-fluorobenzoyloxy,4-toluoyloxy, 4-chlorobenzoyloxy, 4-methoxybenzoyloxy and1-naphthoyloxy; arylalkylcarbonyloxy group such as phenylacetoxy,4-fluorophenylacetoxy, 3-phenylpropanoyloxy, 4-phenylbutanoyloxy andcinnamoyloxy; alkyloxyl group such as methoxy, ethoxy, propoxy,isopropoxy and butoxy; and an alkyloxyiminoalkyl group such as groups ofthe formula: ##STR8## mono- or di-alkylamino, mono- ordi-alkylcarbonylamino or N-alkyl-N-alkylcarbonylamino group such asmethylamino, ethylamino, dimethylamino, diethylamino, acetylamino,pivaloylamino, N-methylacetylamino and N-ethylacetylamino.

Further, preferably Y and Z taken together represent a morpholino groupand thiomorpholino group.

Suitable specific examples of pyrrolo[2,3-d]pyrimidine of the generalformula I in accordance with the present invention include the compoundscontaining the substitUents described in the following table. Note, whenthe compound has asymmetric carbon atoms in structure thereof, thecompounds of the present invention include all optical isomers.

                                      TABLE                                       __________________________________________________________________________     ##STR9##                                                                     Com-                                                                          pound                                                                         No. R.sup.1     R.sup.2 R.sup.3                                                                              R.sup.4                                                                          R.sup.5                                                                          Y        Z                               __________________________________________________________________________    101 H           H                                                                                      ##STR10##                                                                           H  H                                                                                 ##STR11##                                                                             F.sub.2 BH.sup.1)               102 H           H                                                                                      ##STR12##                                                                           CH.sub.3                                                                         CH.sub.3                                                                          ##STR13##                                                                             F.sub.2 BH.sup.1)               103 CH.sub.3    H       CH.sub.3                                                                             H  H                                                                                 ##STR14##                                                                             F.sub.2 BH.sup.1)               104 CH.sub.3    H                                                                                      ##STR15##                                                                           H  H                                                                                 ##STR16##                                                                             H                               105 CH.sub.3    H                                                                                      ##STR17##                                                                           H  H                                                                                 ##STR18##                                                                              ##STR19##                      106 CH.sub.3    H                                                                                      ##STR20##                                                                           H  H                                                                                 ##STR21##                                                                             CO.sub.2 H                      107 CH.sub.3    H                                                                                      ##STR22##                                                                           H  H                                                                                 ##STR23##                                                                             H                               108 CH.sub.3    H                                                                                      ##STR24##                                                                           Cl H                                                                                 ##STR25##                                                                             H                               109 CH.sub.3    H                                                                                      ##STR26##                                                                           H  H                                                                                 ##STR27##                                                                              ##STR28##                      110 CH.sub.3    H                                                                                      ##STR29##                                                                           H  H                                                                                 ##STR30##                                                                              ##STR31##                      111 CH.sub.3    H                                                                                      ##STR32##                                                                           H  H                                                                                 ##STR33##                                                                             F.sub.2 BH.sup.1)               112 CH.sub.3    H                                                                                      ##STR34##                                                                           CH.sub.3                                                                         H                                                                                 ##STR35##                                                                             F.sub.2 BH.sup.1)               113 CH.sub.3    H                                                                                      ##STR36##                                                                           H  H                                                                                 ##STR37##                                                                              ##STR38##                      114 CH.sub.3    H                                                                                      ##STR39##                                                                           H  H                                                                                 ##STR40##                                                                              ##STR41##                      115 CH.sub.3    H                                                                                      ##STR42##                                                                           H  H                                                                                 ##STR43##                                                                             CO.sub.2 H                      116 CH.sub.3    H                                                                                      ##STR44##                                                                           H  H                                                                                 ##STR45##                                                                             CO.sub.2 -iPr                   117 CH.sub.3    H                                                                                      ##STR46##                                                                           H  H                                                                                 ##STR47##                                                                             OH                              118 CH.sub.3    H                                                                                      ##STR48##                                                                           H  H                                                                                 ##STR49##                                                                             OCH.sub.2 CH.sub.3              119 CH.sub.3    H                                                                                      ##STR50##                                                                           H  H                                                                                 ##STR51##                                                                             OAc                             120 CH.sub.3    H                                                                                      ##STR52##                                                                           H  H                                                                                 ##STR53##                                                                              ##STR54##                      121 CH.sub.3    H                                                                                      ##STR55##                                                                           H  H                                                                                 ##STR56##                                                                             NHCH.sub.2 CH.sub.3             122 CH.sub.3    H                                                                                      ##STR57##                                                                           H  H                                                                                 ##STR58##                                                                             NHAc                            123 CH.sub.3    H                                                                                      ##STR59##                                                                           H  H                                                                                 ##STR60##                                                                              ##STR61##                      124 CH.sub.3    H                                                                                      ##STR62##                                                                           H  H                                                                                 ##STR63##                               125 CH.sub.3    H                                                                                      ##STR64##                                                                           H  H                                                                                 ##STR65##                               126 CH.sub.3    H                                                                                      ##STR66##                                                                           H  H                                                                                 ##STR67##                                                                             CH.sub.3                        127 CH.sub.3    H                                                                                      ##STR68##                                                                           CH.sub.3                                                                         CH.sub.3                                                                          ##STR69##                                                                             CH.sub.3                        128 CH.sub.3    H                                                                                      ##STR70##                                                                           H  H                                                                                 ##STR71##                                                                             CH.sub.2 CH.sub.3               129 CH.sub.3    H                                                                                      ##STR72##                                                                           H  H                                                                                 ##STR73##                                                                              ##STR74##                      130 CH.sub.3    H                                                                                      ##STR75##                                                                           H  H                                                                                 ##STR76##                                                                              ##STR77##                      131 CH.sub.3    H                                                                                      ##STR78##                                                                           H  H                                                                                 ##STR79##                                                                              ##STR80##                      132 CH.sub.3    H                                                                                      ##STR81##                                                                           H  H                                                                                 ##STR82##                                                                              ##STR83##                      133 CH.sub.3    H                                                                                      ##STR84##                                                                           H  H                                                                                 ##STR85##                                                                             F.sub.2 BH.sup.1)               134 CH.sub.3    H                                                                                      ##STR86##                                                                           H  H                                                                                 ##STR87##                                                                             F.sub.2 BH.sup.1)               135 CH.sub.3    H                                                                                      ##STR88##                                                                           H  H                                                                                 ##STR89##                                                                              .sup.2)                        136 CH.sub.3    CH.sub.3                                                                               ##STR90##                                                                           H  H                                                                                 ##STR91##                                                                             F.sub.2 BH.sup.1)               137 CH.sub.3                                                                                   ##STR92##                                                                             ##STR93##                                                                           H  H                                                                                 ##STR94##                                                                             F.sub.2 BH.sup.1)               138 CH.sub.3    Ac                                                                                     ##STR95##                                                                           H  H                                                                                 ##STR96##                                                                             OAc                             139 CH.sub.3    H       MMTr.sup.3)                                                                          H  H                                                                                 ##STR97##                                                                              ##STR98##                      140                                                                                ##STR99##  H                                                                                      ##STR100##                                                                          H  H                                                                                 ##STR101##                                                                            F.sub.2 BH.sup.1)               141                                                                                ##STR102## H                                                                                      ##STR103##                                                                          H  H                                                                                 ##STR104##                                                                            F.sub.2 BH.sup.1)               142                                                                                ##STR105## H                                                                                      ##STR106##                                                                          H  H                                                                                 ##STR107##                                                                            F.sub.2 BH.sup.1)               143                                                                                ##STR108## H                                                                                      ##STR109##                                                                          H  H                                                                                 ##STR110##                                                                            F.sub.2 BH.sup.1)               144                                                                                ##STR111## H                                                                                      ##STR112##                                                                          H  H                                                                                 ##STR113##                                                                             ##STR114##                     145                                                                                ##STR115##                                                                                ##STR116##                                                                            ##STR117##                                                                          H  H                                                                                 ##STR118##                                                                            F.sub.2 BH.sup.1)               146                                                                                ##STR119## H                                                                                      ##STR120##                                                                          H  H                                                                                 ##STR121##                                                                            F.sub.2 BH.sup.1)               147                                                                                ##STR122##                                                                                ##STR123##                                                                           H      H                                                                                 ##STR124##                                                                       ##STR125##                              148 CH.sub.3    H                                                                                      ##STR126##                                                                          H  H  NH                                                                                      ##STR127##                     149 CH.sub.3    H                                                                                      ##STR128##                                                                          H  H  NH       H                               150 CH.sub.3    H                                                                                      ##STR129##                                                                          H  H  NH                                                                                      ##STR130##                     151 CH.sub.3    H                                                                                      ##STR131##                                                                          H  H  NH                                                                                      ##STR132##                     152 CH.sub.3    H                                                                                      ##STR133##                                                                          H  H  NH                                                                                      ##STR134##                     153 CH.sub.3    H                                                                                      ##STR135##                                                                          H  H  NH                                                                                      ##STR136##                     154 CH.sub.3    H                                                                                      ##STR137##                                                                          H  H  NH                                                                                      ##STR138##                     155 CH.sub.3    H                                                                                      ##STR139##                                                                          H  H  NH                                                                                      ##STR140##                     156 CH.sub.3    H                                                                                      ##STR141##                                                                          H  H  NH                                                                                      ##STR142##                     157 CH.sub.3    H                                                                                      ##STR143##                                                                          H  H  NH                                                                                      ##STR144##                     158 CH.sub.3    H                                                                                      ##STR145##                                                                          H  H  NH                                                                                      ##STR146##                     159 CH.sub.3    H                                                                                      ##STR147##                                                                          CH.sub.3                                                                         CH.sub.3                                                                         NH                                                                                      ##STR148##                     160 CH.sub.3    H                                                                                      ##STR149##                                                                          H  H  NH                                                                                      ##STR150##                     161 CH.sub.3    H                                                                                      ##STR151##                                                                          H  H  NH                                                                                      ##STR152##                     162 CH.sub.3    H                                                                                      ##STR153##                                                                          H  H  NH                                                                                      ##STR154##                     163 CH.sub.3    H                                                                                      ##STR155##                                                                          H  H  NH                                                                                      ##STR156##                     164 CH.sub.3    H                                                                                      ##STR157##                                                                          H  H  NH                                                                                      ##STR158##                     165 CH.sub.3    H                                                                                      ##STR159##                                                                          H  H  N(CH.sub.3)                                                                            CH.sub.3                        166 CH.sub.3    H                                                                                      ##STR160##                                                                          H  H  N(CH.sub.3)                                                                             ##STR161##                     167 CH.sub.3    H                                                                                      ##STR162##                                                                          H  H  N(CH.sub.3)                                                                             ##STR163##                     168 CH.sub.3    H                                                                                      ##STR164##                                                                          H  H  N(CH.sub.2 CH.sub.3)                                                                    ##STR165##                     169 CH.sub.3    H                                                                                      ##STR166##                                                                          H  H  NH                                                                                      ##STR167##                     170 CH.sub.3    H                                                                                      ##STR168##                                                                          H  H  NH                                                                                      ##STR169##                     171                                                                                ##STR170## H                                                                                      ##STR171##                                                                          H  H  N(CH.sub.3)                                                                            CH.sub.3                        172 CH.sub.3    H                                                                                      ##STR172##                                                                          H  H  NH                                                                                      ##STR173##                     173 CH.sub.3    H                                                                                      ##STR174##                                                                          H  H  NH                                                                                      ##STR175##                     174 CH.sub.3    H                                                                                      ##STR176##                                                                          H  H  NH                                                                                      ##STR177##                     175 CH.sub.3    H                                                                                      ##STR178##                                                                          H  H  NH                                                                                      ##STR179##                     176 CH.sub.3    H                                                                                      ##STR180##                                                                          H  H  NH       CH(CH.sub.3).sub.2              177 CH.sub.3    H                                                                                      ##STR181##                                                                          H  H  NH       CH.sub.2 CH(CH.sub.3).sub.2                                                   4                               178 CH.sub.3    H                                                                                      ##STR182##                                                                          H  H  NH       C(CH.sub.3).sub.3               179 CH.sub.3    H                                                                                      ##STR183##                                                                          H  H  NH                                                                                      ##STR184##                     180 CH.sub.3    H                                                                                      ##STR185##                                                                          H  H                                                                                 ##STR186##                                                                            OCH.sub.3                       181 CH.sub.3    H                                                                                      ##STR187##                                                                          H  H                                                                                 ##STR188##                                                                            C.sub.2 H.sub.4 OC.sub.2                                                      H.sub.5                         182 CH.sub.3    H                                                                                      ##STR189##                                                                          H  H                                                                                 ##STR190##                                                                            CH.sub.3                        183 CH.sub.3    H                                                                                      ##STR191##                                                                          H  H                                                                                 ##STR192##                                                                            CH.sub.3                        184 CH.sub.3    H                                                                                      ##STR193##                                                                          H  H  NH                                                                                      ##STR194##                     185 CH.sub.3    H                                                                                      ##STR195##                                                                          H  H  NH                                                                                      ##STR196##                     186 CH.sub.3    H                                                                                      ##STR197##                                                                          H  H  NH                                                                                      ##STR198##                     187 CH.sub.3    H                                                                                      ##STR199##                                                                          H  H  NH                                                                                      ##STR200##                     188 CH.sub.3    H                                                                                      ##STR201##                                                                          H  H  NH                                                                                      ##STR202##                     189 CH.sub.3    H                                                                                      ##STR203##                                                                          H  H  N(CH.sub.3)                                                                             ##STR204##                     190 CH.sub.3    H                                                                                      ##STR205##                                                                          H  H  NH                                                                                      ##STR206##                     __________________________________________________________________________     wherein F.sub.2 BH.sup.1),  .sup.2) and MMTr.sup.3) represent                 ##STR207##                                                                    ##STR208##                                                                    ##STR209##                                                               

The pyrrolo[2,3-d]pyrimidine derivatives in accordance with the presentinvention may be acid addition salts, and suitable examples of acidsforming such salts include inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, boricacid, carbonic acid, and the like; organic carboxylic acids such asformic acid, acetic acid, propionic acid, citric acid, succinic acid,maleic acid, oxalic acid, tartaric acid, maleic acid, fumaric acid, andthe like; and organic acids such as methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, p-toluene-sulfonic acid, camphorsulfonicacid, and the like.

According to the present invention, a pyrrolo[2,3-d]pyrimidinederivative and pharmaceutically acceptable acid addition salt thereofcan be produced by reacting a halogenated pyrrolo[2,3-d]pyrimidinederivative, or acid addition salt, represented by the general formula II##STR210## wherein R¹, R², R³, R⁴ and R⁵ have the meanings defined inthe formula I of claim 1, and X represents a halogen atom with an aminecompound represented by the general formula III

    Z--Y--H                                                    (III)

wherein Y and Z have the same meanings as defined in the above formulaI, followed by mixing with an inorganic or organic acid, if necessary.

The halogenated pyrrolo[2,3-d]pyrimidine derivative represented by theformula II (wherein R¹ to R⁵ have the meanings defined above inconnection with the R¹ to R⁵ in the formula I and X represents a halogenatom) may be a novel or known compound. With respect to the knowncompound, a process for producing same is also known in the art (see,for example, F. Seela et al., Liebigs Ann. Chem., 137 (1983); and M.Legraverend et al., Tetrahedron Lett., Vol. 26, 2001 (1985)).

Also a novel compound can be prepared according to a process ofproducing a similar known compound. Examples of the halogen atom in thehalogenated pyrrolo[2,3-d]pyrimidine derivative include a chlorine atom,a bromine atom and an iodine atom. Such atoms are highly reactive, and apyrrolo[2,3-d]pyrimidine derivative of interest, represented by theformula I, can be produced by reacting such atoms with a amine compoundrepresented by the formula III wherein Y and Z have the meanings definedabove in connection with the Y and Z in the formula I.

The amine compound represented by the formula III, as such, is known inthe art, or may be produced according to a known process. Suitablespecific examples of the above-described amine compound, when Yrepresents a linking group of the formula: ##STR211## includepyrrolidine, 2-methylpyrrolidine, 2-hydroxymethylpyrrolidine,2-benzylpyrrolidine, 2-phenylpyrrolidine, 2-carboxypyrrolidine and2-methoxycarbonylpyrrolidine; when Y represents a linking group of theformula: ##STR212## include piperidine, 2-methylpiperidine,2-hydroxymethylpiperidine, 2-benzylpiperidine, 2-phenylpiperidine,2-carboxypiperidine and 2-methoxycarbonylpiperidine; when Y represents alinking group of the formula: ##STR213## include 2,6-dimethylpiperidine;when Y represents a linking group of the formula: ##STR214## include4-hydroxypiperidine, 4-methylpiperidine, 4-ethylpiperidine,4-benzylpiperidine, 4-(4-fluorobenzyl)piperidine,4-[bis(4-fluorophenyl)methyl]piperidine, 4-phenylpiperidine,4-acetyloxypiperidine, 4-propanoyloxypiperidine, 4-benzoyloxypiperidine,4-(4-fluorobenzoyloxy)piperidine, 4-(4-chlorobenzoyloxy)piperidine,4-(phenylacetyloxy)piperidine, 4-acetylpiperidine,4-propanoylpiperidine, benzoylpiperidine,4-(1-methoxyimino)ethylpiperidine, 4-carboxypiperidine,4-isopropyloxycarbonylpiperidine, 4-methoxypiperidine,4-ethoxypiperidine, 4-(methylamino)piperidine,4-(N,N-dimethylamino)-piperidine, 4-(acetylamino)piperidine and4-(N-methyl-N-acetylamino)piperidine; when Y represents a linking groupof the formula: ##STR215## include N-methylpiperazine,N-(2-methoxyethyl)piperazine, N-allylpiperazine, N-phenylpiperazine,N-benzylpiperazine, N-(4-fluorophenyl)piperazine,N-(4-fluorobenzyl)piperazine, N-(2-phenylethyl)piperazine,N-[2-[2-(trifluoromethyl)phenyl]ethyl]piperazine, N-cinnamylpiperazine,N-[bis(4-fluorophenyl)methyl]piperazine, N-acetylpiperazine,N-(4-fluorobenzoyl)piperazine, N-(4-chlorobenzoyl)piperazine,N-(4-fluorophenylacetyl)piperazine and N-cinnamoylpiperazine; and when Yrepresents a linking group of the formula: ##STR216## includeN-methyl-perhydro[1,4]diazepine, N-allyl-perhydro[1,4]diazepine,N-benzyl-perhydro[1,4]diazepine,N-(2-phenylethyl)perhydro[1,4]diazepine,N-[bis(4-fluorophenyl)methyl]perhydro[1,4]diazepine andN-acetyl-perhydro[1,4]diazepine; when Y represents a linking group ofthe formula: --NH--, include ammonia, allylamine, 2-methylallylamine,methylamine, isopropylamine, isobutylamine, tert-butylamine,1,3-dimethoxy-2-propylamine, tetrahydrofurfurylamine,2-(N,N-dimethylamino)ethylamine, 2-morpholinoethylamine,2-piperidinoethylamine, 2-(3,5-dimethoxyphenoxy)ethylamine,trans-4-hydroxycyclohexylamine, cyclohexylamine,trans-4-methoxycyclohexyalmine, cis-4-methoxycyclohexylamine,trans-4-(2-ethoxyethoxy)cyclohexylamine, 2-tetrahydrofurylamine,4-tetrahydropyranylamine, benzylamine, 4-fluorobenzylamine,4-chlorobenzylamine, 4-methoxybenzylamine, 1-phenylethylamine,1-methyl-1-phenylethylamine, 2-phenylethylamine,2-(4-fluorophenyl)ethylamine, 2-(4-chlorophenyl)ethylamine,2-(4-methoxyphenyl)ethylamine, 1,1-diphenylmethylamine,1,1-bis(4-fluorophenyl)methylamine, cinnamylamine,1-(1-naphthyl)ethylamine, 1,2,3,4-tetrahydronaphthalene-1-yl amine,furfurylamine, 2-thienylmethylamine, 3-(2-furyl)propylamine; when Yrepresents a linking group of the formula: --N(CH₃)--, --N(C₂ H₅)-- or--N(CH₂ CH₂ OCH₂ CH₃)--, include dimethylamine, diethylamine,N-methylbenzylamine, N-methyl(2-phenylethyl)amine, N-ethylbenzylamine,N-methyl(1-phenylethyl)amine, N-ethyl-(1-phenylethyl)amine,N-methylallylamine and Bis(2-ethoxyethyl)amine; when Y and Z takentogether represent a group --Y--Z, include morpholine andthiomorpholine.

The above-described reaction can be conducted, for example, by reactingone equivalent of a halogenated pyrrolo[2,3-d]pyridine derivativerepresented by the formula II with 1 to 30 equivalents of a aminecompound represented by the formula III in the absence or presence of asolvent. If necessary, a base also may be present in the reactionsystem, and examples of the base include inorganic bases such as sodiumhydroxide, potassium hydroxide, sodium carbonate and potassiumcarbonate, and organic bases such as triethylamine, diethylaniline,dimethylaniline and pyridine.

The reaction temperature is from -20° to 300° C., preferably from a roomtemperature to 200° C. and the reaction time is usually 72 hours orless.

Examples of the reaction solvent include halogenated hydrocarbons suchas dichloromethane, chloroform, trichloroethane and carbontetrachloride; aromatic hydrocarbons such as benzene, toluene andxylene; alcohols such as methanol, ethanol, isopropyl alcohol, butanoland tert-butanol; ethers such as diethyl ether, tetrahydrofuran anddioxane; and aprotic polar solvents such as dimethylformamide,dimethylacetamide, dimethylsulfoxide and sulfolane.

After the completion of the reaction, the desired product, apyrrolo[2,3-d]pyrimidine derivative represented by the formula I, can beisolated by general separating and purifing procedure, i.e.,concentration, extraction, recrystallization, and chromatography, etc.The compound I can be also converted to a pharmaceutically acceptableacid addition salt according to a conventional method.

The entire steps of the reaction, including general steps utilized forproducing the above-described starting material of the formula II, areas follows: ##STR217## wherein R¹, R², R³, R⁴ and R⁵, as well as X, Yand Z, have the meanings as defined above, and TBDMSOTf representstert-butyl-dimethyl-silyl-trifluoromethanesulfonate.

The reaction steps for the compound of formula II are summarized asfollows:

The compound of the formula (3) can be obtained by a reaction of acetal(1) with ethyl cyanoacetate (2) in an alkaline condition, following by aring-closing reaction using guanidine in the presence of a strong base.

The compound of formula (4) can be obtained by a ring-closing reactionof the resulting compound (3) in the presence of hydrochloric acid,followed by a halogenation according to a usual method, e.g., withphosphorus oxychloride.

The compound of formula (5) can be obtained by a silylation of theresulting compound (4) with TBDMSOTf, followed by a reaction with R¹ X,wherein X is a halogen atom, in an alkaline condition.

The compound of formula (6) can be obtained by a reaction of theresulting compound (5) with R⁵ X in the presence of a strong base,followed by a desilylation with hydrochloric acid.

The compounds, to which are selectively introduced the substituents R¹,R² and R³, of the formula II can be obtained by a reaction of the finalcompound (6) with R³ X, in the presence of a strong base.

The present compounds exhibit an excellent pharmacological actionagainst hypoxemia associated with various respiratory diseases. It isgenerally known that, in pneumonopathy, e.g., pneumonectasis,bronchitis, bronchial asthma, interstitial preumonia andpneumonophthisis, the partial pressure of oxygen (PaO₂) in arterialblood lowers according as the pathosis is severer or chronic. In thiscase, symptoms such as a feeling of fatigue, shortness of breath andchoking feeling occur, and in a serious state, dyspnea, cyanosis and adisturbance of consciousness occur.

Therefore, a pharmaceutical preparation capable of raising and improvingthe PaO₂ lowered due to such respiratory diseases has been desired inthe art. Further, it is often shown that, in such diseases, the partialpressure of carbon dioxide (PaCO₂) in arterial blood increasesconversely to a decrease of PaO₂, and in this case, there is a need fora pharmaceutical preparation that can not only increase PaCO₂ but alsodecrease PaO₂.

The compounds in accordance with the present invention have actions suchthat they enhance the respiratory function of the lung, that one mainlyincreases only PaO₂, and that another increases PaO₂ and decreasesPaCO₂, at the same time, and thus the present compounds are useful forthe treatment of hypoxemia associated with various respiratory diseases.

The pharmacological effect of the compound in accordance with thepresent invention can be demonstrated by an acute hypoxemia model usingan experimental animal. For example, the acute hypoxemia (having a lowerPaO₂ value) model can be prepared by administering intratracheally afine powder, such as carbon powder, silica gel, glass beads or dentalimpression material, in a small animal, e.g., rat, to lower therespiratory function (see, for example, Munakata et al., Preprints ofthe 35th Symposium of Japan Society of Anesthesiology, 179 (1988)). Alsothe acute hypoxemia (having a lower PaO₂ value) model can be prepared byadministering intratracheally a mucosa-prophiogistic acid, e.g., aceticacid and crotonic acid. Therefore, the compounds in accordance with thepresent invention were orally or parenterally administered to theabove-described model animal, and the arterial blood was collected aftera given period of time and subjected to a measurement of PaO₂ (or PaCO₂)by a blood gas analyzer. As a result, a significant increase of PaO₂ (ordecrease of PaCO₂) in comparison with that before the administration,was observed.

The pyrrolo[2,3-d]pyrimidine derivative and its acid addition salt inaccordance with the present invention can be administered orally or as aparenteral administration such as an intravenous, subcutaneous,intramuscular, percutaneous, intrarectal or other administration.

Examples of the dosage form for the oral administration include tablets,pills, granules, powders, suspensions and capsules.

The tablets can be formulated by a conventional method through the useof, for example, excipients such as lactose, starch and crystallinecellulose; binders such as carboxymethylcellulose, methylcellulose andpolyvinylpyrrolidone; and disintegrators such as sodium alginate, sodiumhydrogencarbonate and sodium laurylsulfate.

Similarly, the pills, powders and granules can be formulated by aconventional method through the use of the above-described excipients,etc. The solutions and suspensions can be formulated by a conventionalmethod through the use of, for example, glycerin esters such astricaprylin and triacetin and alcohols such as ethanol. The capsules canbe formulated by filling a granule, a powder or a solution into acapsule made of gelatin, and the like.

Examples of the dosage form for a subcutaneous, intramuscular andintravenous administration include injections in the form of an aqueousor nonaqueous solution. In the aqueous solution, use is made of, forexample, a physiological saline, and the like. In the nonaqueoussolution, use is made of, for example, propylene glycol, polyethyleneglycol, olive oil, ethyl oleate, and the like. If necessary,preservatives, stabilizers, etc., may be added thereto. The injectionscan be sterilized by a proper treatment, such as a filtration throughthe bacterial filter, or by an addition of a bacteriocide.

Examples of the dosage forms for a percutaneous administration includeointments and creams. The ointments and creams can be formulated by aconventional method through the use of fatty oils, such as castor oiland olive oil, petrolatums, etc., in the case of the ointments, andemulsifiers, such as diethylene glycol and sorbitan monofatty acidesters, etc., in the case of the creams.

Conventional suppositories, such as gelatin soft capsules, may be usedfor a rectal administration.

Although the dosage of the pyrrolo[2,3-d]pyrimidine derivative of thepresent invention varies depending upon the kind of disease,administration path, age and sex of patient, and severity of disease,etc., it is usually 1 to 500 mg/day/adult.

All of the compounds provided by the present invention (testingsubstances) have more than 2 g/kg (rat, P.O.) of LD₅₀.

EXAMPLES

The present invention will now be described in more detail withreference to the following Examples.

Reference Example Synthesis of2-allylamino-4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine

Procedure A:

A mixture of 5.00 g (29.6 mmol) of2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine, 10.08 g (1.1 eq.) ofp-anisylchlorodiphenylmethane, and 4.96 ml (12 eq.) of triethylamine in65 ml of dimethylformamide (DMF) was stirred at room temperature for 30min. After cooling to 0° C., 4.50 ml (2.44 eq.) of methyliodide and 3.00g (2.53 eq.) of sodium hydride were added in order, and the mixture wasstirred for one hour. And then, 5.36 ml (1.5 eq.) of allyl iodide and2.00 (2.5 eq.) of sodium hydride were added to the reaction mixturefollowed by additional one hour stirring at 0° C. Finally 200 ml of 2Nhydrochloric acid and 100 mI of diethyl ether were added and stirred forone hour at room temperature. The reaction mixture was neutralized withsodium bicarbonate and extracted with three portion of 100 ml ofethylacetate. The combined organic layer was washed with brine, driedover anhydrous magnesium sulfate. The solvents were removed in vacuo.The residual oily mixture was purified with silica-gel columnchromatography (hexane: ethylacetate=8:1 as elutant), to give 3.51 g(53.1%) of 2-allylamino-4-chloro-7-methyl-7H-pyrrdo[2,3-d]pyrimidine.

Procedure B:

To 300 ml of methylene chloride was added 26.9 g (159.5 mmol) of2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 111 ml (5 eq.) oftriethylamine, and the mixture was stirred at -30° C. Then 36.7 ml (1.1eq.) of tert-butyldimethylsillyl trifluoromethane sulfonate was slowlydropwised to the mixture, and reacted for 1.5 hours. The crystals werecompletely dissolved to form a light brown solution. The mixture wasallowed to worm to room temperature and filtrated with 200 g ofsilica-gel on a glass-filter. The filtrate and an elute eluted with 1 lof methylene chloride was combined. After evaporation of the solution,to the oily residue was added 300 ml of aqueous 1N NaOH, and the aqueoussolution was extracted with hexane (500 ml×4). The combined organiclayer was washed with water and brine in order, dried over anhydrousmagnesium sulfate, and removed the solvents in vacuo. The resultingcrystals were recrystallized from hexane, to give 35.27 g (yield 78.2%)of 2-tert-butyl-dimethylsilylamino-4-chloro-7H-pyrrolo[2,3-d]pyrimidinein the form of light brown plates (m.p. 114° C.)

Physical Property:

¹ H-NMR (CDCl₃) δ:

0.30(s, 6H), 0.98(s, 9H), 4.5(br-s, 1H)

6.4H(m, 1H) 6.9(m, 1H), 8.3(br-s, 1H)

Then, 44.0 g (115.6mmol) oftert-butyldimethylsilylamino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine and13.5 ml (1.4 eq.) of methyl iodide in 150 ml of DMF, and 34.40 g (1.6eq.) of potassium carbonate was reacted at room temperature for 15 hourswith vigorous stirring. After addition of water to the reaction mixture,the aqueous solution was extracted with hexane (200 ml×4), washed withbrine, and dried over anhydrous magnesium sulfate. The solvents wereremoved in vacuo, to give 45.87 g (154.5 mmol) (quantitative yield) of2-ter-butyl-dimethylsilylamino-4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidinein the form of light yellow crystals. Under nitrogen atmosphere thecrystals and 21.19 ml (1.5 eq.) of allyl iodide were dissolved in 300 mlof DMF, and the reaction mixture was cooled to 0° C. with vigorousstirring, then 9.27 g (1.5 eq.) of sodium hydride (60%), thoroughlywashed by hexane, was added to that as hexane suspension.

The mixture was stirred for 10 min., and then 300 ml of water was slowlyadded to stop the reaction. The aqueous solution was extracted withhexane (300 ml×4), the combined organic layer was washed with water andbrine, and dried over anhydrous magnesium sulfate. After evaporation,53.5 g of a yellow oily residue was given. The residue was dissolved in30 ml of diethylether, acid to the solution 50 ml of concentratedhydrochloric acid was added at 0° C. with stirring, and the mixture wasreacted for 10 min. After the reaction was completed, to the solutionwas added diethylether (100 ml×2) to separate the organic layer. Theaqueous layer was diluted with 200 ml of ice-water, and then neutralizedwith a 5N NaOH aqueous solution.

The Resulting precipitate was extracted with ethylacetate (250 ml×3),the extract was washed with water and brine, dried over anhydrousmagnesium sulfate, and evaporated, to give 33.57 g (yield 97.6%) of2-allylamino-4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in the formof light yellow crystals.

The crystals were recrystallized from ethylalcohol to give 32.57 g(yield 94.0%) of the above-described compound as yellowish white plates(m.p. 113°-114° C.)

Physical Properties:

¹ H-NMR (CDCl₃), δ: 3.67(s, 3 H), 4.0-4.2(m, 2H), 3.9-5.4(m, 3H).5.75-6.25(m, 1H), 6.34(d, 1H, J=3.5 Hz), 6.77(d, 1H, J=3.5 Hz).

Elemental analysis: for C₁₀ H₁₁ N₄ Cl, Calculated: C, 53.94; H, 4.98; N,25.16 Found: C, 53.90; H, 4.98; N, 25.11

Example 1 Synthesis of(±)-2-allylamino-7-methyl-4-(1-phenylethyl-amino]-7H-pyrrolo[2,3-d]pyrimidineand its hydrochloride (156)

To 70 ml of n-butylalcohol was added 32.5 g (146.0 mmol) of2-allylamino-4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine prepared inReference Example, 26.22 g (1.3 eq.) of potassium carbonate and 88 g(5.0 eq.) of (±)-phenyl-ethylamine, the mixture was stirred in anautoclave equipped with a stirrer at 165° C. (5 atm) for 5 hours. Aftercooling to room temperature, 400 ml of water was added, and the mixturewas extracted with ethylacetate (250 ml×3). Combined organic layer waswashed with water and brine, dried over anhydrous magnesium sulfate, andthen the solvents and unreacted (±)-phenylethyl-amine were removed invacuo. The red oily residue was crystallized with isopropylalcohol, togive 40.38 g (yield 90.0%) of(±)-2-allylamino-7-methyl-4-(1-phenylethyl-amino)-7H-pyrrolo[2,3-d]pyrimidine[(156) free base] in the form of crude crystals. They wererecrystallized from isopropylalcohol to give 37.56 g (yield 83.7%) ofcolorless needles (m.p. 112°-112.5° C.). Then 30.00 g of the free basewas dissolved in 800 ml of diethylether, and a saturated hydrochloricacid ethereal solution was added to form hydrochloride.

The diethylether and excess hydrochloric acid were evaporated and theresulting oily residue was crystallized with acetone.

The crystals were washed with acetone, and dried in vacuo at 80° C., togive 33.08 g (yield from the free base, 98.6%) of(±)-2-allylamino-7-methyl-4-(1-phenylethylamino)-7H-pyrrolo[2,3-d]pyrimidinehydrochloride [(156) HCl.salt] in the form of colorless crystals (m.p.167°-170° C.).

Physical Properties

The Free Base

¹ H-NMR (CDCl₃) δ:

1.60 (d, 3H, J=6,8), 3.60(s, 3H), 4.0(t, 2H, J=5.7), 4.65(br-t, 1H,J=5,7), 4.95(br-s, 1H), 4.9-5.4(m, 2H), 5.43(t, 1H, J=6.8), 5.7-6.2(m,1H), 6.11(d, 1H, J=3.5), 6.54(d, 1H, J=3.5), 7.2-7.5(m, 5H)

IR(KBr) vmax, cm⁻¹ 3240, 1620, 1560, 1450, 1285

UV(EtOH) λmax, nm 295, 228

Elemental analysis: for C₁₅ H₂₁ N₅, Calculated: C, 70.33; H, 6.89; N,22.78. Found: C, 70.38; H, 7.01; N, 22.63.

The Hydrochloride

IR(KBr) vmax, cm⁻¹ 3240, 1620, 1560, 1450, 1285

UV(EtOH) λmax, nm 296, 236, 207

Elemental analysis: for C₁₈ H₂₂ N₅ Cl, Calculated: C, 62.87; H, 6.45; N,20.37; Cl, 10.26 Found: C, 62.84; H, 6.40; N, 20.23; Cl, 10.29.

In the following Examples, the compounds of the present invention wereprepared by the procedures described in Example 1, using correspondingstarting materials and reactants, respectively, as well as reactionsolvents and coexisting bases indicated in the following tables, andeach reaction was performed under the condition, i.e., reactiontemperature, reaction times, and reaction vessel, indicated in saidtables.

    __________________________________________________________________________                                         Type of salt                                                                          UV of acid                                                        Yield                                                                             M.P. of acid                                                                          addition                                                                            Reaction                                                                           Reaction temp.           Com-                          of free                                                                           addition salt                                                                         salt  solvent                                                                            Reaction time         Ex.                                                                              pound                                                                             H-NMR data of free base,  base                                                                              Recrystallization                                                                     EtOH  Coexisting                                                                         Reaction              No.                                                                              No. (CDCl.sub.3) δ (ppm)                                                                              (%) solvent λ max                                                                        base vessel                __________________________________________________________________________    2  101 2.47(t-like, 4H, J=5Hz), 3.7-4.1(m, 6), 4.25(s, 1H),                                                    71  HCl.salt                                                                              299   n-BuOH                                                                             120° C.               4.9-5.3(m, 3H), 5.7-6.1(m, 1H), 6.28(d, 1H, J=3.7Hz),                                                       180-184° C.                                                                    233   K.sub.2 CO.sub.3                                                                   14 h                         6.70(d, 1H, J=3.7Hz), 6.8-7.5(m, 9H)                                                                        (dec.)  207        B                                                          i-PrOH                                   3  103 2.46(t-like, 4H, J=5Hz), 2.9-3.0(m, 3H), 3.61(s,                                                        74),                                                                              HCl.salt                                                                              --    n-BuOH                                                                             120° C.               3.88(t-like, 4H, J=5Hz), 4.23(s, 1H), 4.3-4.7(m,                                                                          K.sub.2 CO.sub.3                                                                   5 h                          6.23(d, 1H, J=3.6Hz), 6.56(d, 1H, J=3.6), 6.8-7.5(m,                                                                           BH)                   4  104 1.9-2.1(m, 4H), 3.62(s, 3H), 3.6-3.9(m, 4H),                                                            74  HCl.salt                                                                              302   n-BuOH                                                                             110° C.               4.0-4.2(m, 2H), 4.6(br-s, 1H), 5.0-5.4(m, 2H),                                                              193-195° C.                                                                    267   K.sub.2 CO.sub.3                                                                   8 h                          5.8-6.3(m, 1H), 6.35(d, 1H, J=3.5Hz), 6.54(d, 1H,                                                           i-PrOHz)                                                                              237        B                     5  105 1.8-2.0(m, 4H), 2.7(m, 1H), 3.4(m, 1H), 3.64(s, 3H),                                                    70  HCl.salt                                                                              299   none 145° C.               3.8(m, br, 3H), 4.17(m, 2H), 4.7(br, 1H), 5.0-5.4(m,                                                        150-153° C.                                                                    237   K.sub.2 CO.sub.3                                                                   20 h                         5.8-6.3(m, 1H), 6.38(d, 1H, J=3.5Hz), 6.57(d, 1H,                                                           i-PrOHz),                                                                             206        B                            7.25(s, 5H)                                                            6  106 1.9-2.7(m, 4H), 3.57(s, 3H), 3.5-4.4(m, 5H), 4.8(br-1H),                                                21  fumarate                                                                              --    n-BuOH                                                                             100° C.               4.9-5.4(m, 2H), 5.7-6.2(m, 1H), 6.41(d, 1H, J=3.5Hz),                                                       EtOH          K.sub.2 CO.sub.3                                                                   4 h                          6.54(d, 1H, J=3.5Hz), 9.4(br, 1H)                B                     7  107 1.5-2.0(m, 6H), 3.61(s, 3H), 3.8-3.95(m, 4H),                                                           100 HCl.salt                                                                              --    n-BuOH                                                                             110° C.               4.08(t-like, 2H, J=5.5Hz), 4.6(br, 1H), 4.95-5.4(m,                                                         161-162° C.                                                                          --   6 h                          5.8-6.3(m, 1H), 6.31(d, 1H, J=3.5Hz), 6.57(d, 1H,                                                           i-PrOHz)           B                     8  109 1.6-1.7(br, 4H), 1.8-2.5(br, 2H), 3.1(m, 1H), 3.61(s,                                                   45),                                                                              fumarate                                                                              233   --   150° C.               4.05(m, 2H), 4.6(br, 1H), 4.8(br, 1H), 5.0-5.3(m,                                                           158-159° C.                                                                    206   K.sub.2 CO.sub.3                                                                   35 h                         5.8-6.1(m, 1H), 6.1(br, 1H), 6.16(d, 1H, J=3.5Hz),                                                          EtOH               B                            6.51(d, 1H, J=3.5Hz), 7.30(s-like, 5H)                                 9  110 1.1-1.9(m, 5H), 2.54(d, 2H), J=6.6Hz), 2.92(t, 2H,                                                      1001Hz),                                                                          --      --    n-BuOH                                                                             120° C.               3.60(s, 3H), 4.06(t, 2H, J=6Hz), 4.5-4.7(m, 3H),                                                                          K.sub.2 CO.sub.3                                                                   5 h                          4.9-5.4(m, 2H), 5.7-6.2(m, 1H), 6.27(d, 1H, J=3.5Hz),                                                                          B                            6.56(d, 1H, J=3.5Hz), 7.0-7.4(m, 5H)                                   10 113 1.5-2.1(m, 4H), 2.15(s, 3H), 2.4-2.8(m, 1H),                                                            100 fumarate                                                                              --    n-BuOH                                                                             120° C.               2.9-3.35(m, 2H), 3.60(s, 3H), 4.07(t, 2H, J=6Hz),                                                           164-166° C.                                                                          K.sub.2 CO.sub.3                                                                   8 h                          4.5-4.9(m, 3H), 5.0-5.4(m, 2H), 5.7-6.3(m, 1H),                                                             EtOH               B                            6.28(d, 1H, J=3.5Hz), 6.58(d, 1H, J=3.5Hz)                             11 114 1.4-2.0(m, 7H), 2.2-2.65(m, 1H), 2.8-3.2(m, 2H),                                                        30  fumarate                                                                              --    n-BuOH                                                                             120° C.               3.61(s, 3H), 3.82(s, 3H), 4.07(t, 2H, J=6Hz),                                                               133-134° C.                                                                          K.sub.2 CO.sub.3                                                                   4 h                          4.5-5.4(m, 5H), 5.8-6.3(m, 1H), 6.29(d, 1H, J=3.5Hz),                                                       EtOH               B                            6.58(d, 1H, J=3.5Hz)                                                   12 115 1.3-2.1(m, 4H), 2.3-2.7(m, 1H), 2.9-4.7(br, 1H),                                                        98  --      --    n-BuOH                                                                             80° C.                2.95-3.4(m, 2H), 3.58(s, 3H), 3.8-4.1(m, 2H),                                                                             K.sub.2 CO.sub.3                                                                   38 h                         4.3-4.8(m, 2H), 4.9-5.4(m, 2H), 5.6(br-t, 1H, J=6Hz),                                                                          B                            5.8-6.3(m, 1H), 6.29(d, 1H, J=3.5Hz), 6.67(d, 1H, J=3.5Hz)             13 116 1.24(d, 6H, J=6.2Hz), 1.5-2.2(m, 4H), 2.3-2.7(m,                                                        30),                                                                              fumarate                                                                              --    n-BuOH                                                                             120° C.               3.0-3.4(m, 2H), 3.63(s, 3H), 3.9-4.2(m, 2H),                                                                151-153° C.                                                                          K.sub.2 CO.sub.3                                                                   4 h                          4.3-5.4(m, 6H), 5.8-6.4(m, 1H), 6.30(d, 1H, J=3.7),                                                         EtOH               B                            6.60(d, 1H, J=3.7Hz)                                                   14 117 1.3-2.15(m, 4H), 3.38(ddd, 2H, J=13Hz, 9.4Hz, 3.3Hz),                                                   81  fumarate                                                                              301   n-BuOH                                                                             120° C.               3.61(s, 3H), 3.75-4.8(m, 7H), 4.95-5.35(m, 2H),                                                             183-185° C.                                                                    271   K.sub.2 CO.sub.3                                                                   4 h                          5.85-6.2(m, 1H), 6.29(d, 1H, J=3.6Hz), 6.59(d, 1H,                                                          EtOH6)  233        B                     15 118 1.21(t, 3H, J=7.0Hz), 1.3-2.1(m, 4H), 3.2-3.7(m,                                                        30),                                                                              fumarate                                                                              300   n-BuOH                                                                             120° C.               3.61(s, 3H), 3.9-4.4(m, 4H), 4.7(br-t, 1H, J=6Hz),                                                          163-165° C.                                                                    272   K.sub.2 CO.sub.3                                                                   4 h                          4.9-5.35(m, 2H), 5.7-6.3(m, 1H), 6.29(d, 1H, J=3.6Hz),                                                      EtOH    233        B                            6.57(d, 1H, J=3.6Hz)                                                   16 119 1.5-2.2(m, 4H), 2.06(s, 3H), 3.3-3.85(m, 2H), 3.62(s,                                                   30),                                                                              fumarate                                                                              302   n-BuOH                                                                             120° C.               3.9-4.4(m, 4H), 4.68(br-t, 1H, J=6.2Hz), 4.85-5.35(m,                                                       164-166° C.                                                                    271   K.sub.2 CO.sub.3                                                                   4 h                          5.75-6.2(m, 1H), 6.28(d, 1H, J=3.7Hz), 6.60(d, 1H,                                                          i-PrOHz)                                                                              234        B                     17 120 1.8-2.3(m, 4H), 3.63(s, 3H), 3.55-3.9(m, 2H),                                                           30  fumarate                                                                              301   n-BuOH                                                                             120° C.               4.0-4.4(m, 4H), 4.69(br-t, 1H, J=6.2),                                                                      159-164° C.                                                                    271   K.sub.2 CO.sub.3                                                                   4 h                          4.95-5.45(m, 3H), 5.75-6.25(m, 1H), 6.31(d, 1H, J=3.7Hz),                                                   EtOH    233        B                            6.61(d, 1H, J=3.7Hz), 6.95-7.2(m, 2H), 7.9-8.2(m,                                                                   204                              18 121 1.16(t, 3H, J=7.3Hz), 1.2-1.7(m, 2H), 1.8-2.3(m,                                                        88),                                                                              HCl.salt                                                                              --    n-BuOH                                                                             120° C.               2.4-3.3(m, 5H), 3.62(s, 3H), 4.07(t-like, 2H, J=5.7Hz),                                                     185-200° C.                                                                          K.sub.2 CO.sub.3                                                                   4 h                          4.5-4.85(m, 3H), 5.0-5.4(m, 2H), 5.8-6.3(m, 1H),                                                            i-PrOH             B                            6.30(d, 1H, J=3.6Hz), 6.58(d, 1H, J=3.6Hz)                             19 122 1.1-1.2(m, 5H), 1.96(s, 3H), 2.9-3.35(m, 2H), 3.62(s,                                                   77),                                                                              HCl.salt                                                                              --    n-BuOH                                                                             120° C.               3.9-4.2(t-like, 2H, J=6Hz), 4.5-4.8(m, 3H),                                                                 156-158° C.                                                                          K.sub.2 CO.sub.3                                                                   4 h                          5.0.5.4(m, 2H), 5.4(br, 1H); 5.8-6.3(m, 1H),                                                                i-PrOH             B                            6.28(d, 1H, J=3.5Hz), 6.60(d, 1H, J=3.5Hz)                             20 123 1.2-2.7(m, 7H), 2.30(s, 6H), 2.8-3.2(m, 2H), 3.62(s,                                                    96),                                                                              HCl.salt                                                                              --    n-BuOH                                                                             120° C.               4.08(t-like, 2H, J=6Hz), 4.5-4.99(m, 3H),                                                                   i-PrOH        K.sub.2 CO.sub.3                                                                   6 h                          4.95-5.4(m, 2H), 5.8-6.3(m, 1H), 6.31(d, 1H, J=3.5Hz),                                                                         B                            6.59(d, 1H, J=3.5Hz)                                                   21 124 3.63(s, 3H), 3.6-4.0(m, 8H), 4.08(t-like, 2H, J=6Hz),                                                   100 HCl.salt                                                                              --    n-BuOH                                                                             80° C.                4.7(br, 1H), 4.95-5.4(m, 2H), 5.7-6.3(m, 1H),                                                               159-161° C.                                                                          --   14 h                         6.28(d, 1H, J=3.5Hz), 6.61(d, 1H, J=3.5Hz)                                                                  i-PrOH             B                     22 125 2.6-2.8(m, 4H), 3.62(s, 3H), 4.0-4.3(m, 3H),                                                            100 HCl.salt                                                                              302   n-BuOH                                                                             120° C.               4.8(br-t, 1H, J=6Hz), 5.0-5.4(m, 2H), 5.8-6.3(m,                                                            174-176° C.                                                                    237   K.sub.2 CO.sub.3                                                                   6 h                          6.23(d, 1H, J=3.5Hz), 6.61(d, 1H, J=3.5Hz)                                                                  i-PrOH  206        B                     23 126 2.33(s, 3H), 2.50(t, 4H, J=5Hz), 3.62(s, 3H)                                                            100 HCl.salt                                                                              --    n-BuOH                                                                             100° C.               3.91(t, 4H, J=5Hz), 4.08(t-like, 2H, J=6Hz),                                                                190-195° C.                                                                          K.sub.2 CO.sub.3                                                                   6 h                          4.7(br-t, 1H, J=7Hz), 4.95-5.4(m, 2H), 5.75-6.3(m,                                                          i-PrOH             B                            6.30(d, 1H, J=3.7Hz), 6.50(d, 1H, J=3.7Hz)                             24 129 3.20(t, 4H, J=5Hz), 3.6(s, 3H), 3.8-4.1(m, 6H),                                                         89  HCl.salt                                                                              301   n-BuOH                                                                             120° C.               4.67(br-t, 1H, J=6Hz), 4.9-5.3(m, 2H), 5.75-6.1(m,                                                          190-194° C.                                                                    239   K.sub.2 CO.sub.3                                                                   27 h                         6.33(d, 1H, J=3.6Hz), 6.62(d, 1H, J=3.6Hz), 6.7-7.0(m,                                                      EtOH    206        B                     25 130 2.53(t, 4H, J=5Hz), 3.54(s, 2H), 3.61(s, 3H),                                                           26  --      --    n-BuOH                                                                             120° C.               3.7-4.1(m, 6H), 4.6(br-t, 1H, J=6Hz), 4.85-5.3(m,                                                                         K.sub.2 CO.sub.3                                                                   17 h                         5.6-7.2(m, 1H), 6.27(d, 1H, J=3.5Hz), 6.57(d, 1H,                                                                              B=3.5Hz),                    7.0-7.3(m, 5H)                                                         26 131 2.50(t, 4H, J=5Hz), 3.47(s, 2H), 3.60(s, 3H),                                                           89  HCl.salt                                                                              302   n-BuOH                                                                             120° C.               3.7-4.2(m, 6H), 4.69(br-t, 1H, J=6Hz), 4.9-5.4(m,                                                           158-163° C.                                                                    236   K.sub.2 CO.sub.3                                                                   18 h                         5.76-6.25(m, 1H), 6.26(d, 1H, J=3.5Hz),                                                                     EtOH/n-hexane                                                                         206        B                            6.56(d, 1H, J=3.5Hz), 6.8-7.45(m, 4H)                                  27 132 2.4-2.8(m, 6H), 2.8-3.1(m, 2H), 3.62(s, 3H),                                                            83  HCl.salt                                                                              304   n-BuOH                                                                             120° C.               3.7-4.2(m, 6H), 4.71(br-t, 1H, J=6), 4.9-5.4(m, 2H),                                                        160-163° C.                                                                    237   K.sub.2 CO.sub.3                                                                   15 h                         5.75-6.3(m, 1H), 6.31(d, 1H, J=3.7), 6.60(d, 1H,                                                            i-PrOH/EtOH                                                                           207        B                            7.2-7.7(m, 4H)                                                         28 133 2.46(t-like, 4H, J=5Hz), 3.61(s, 3H), 3.75-4.15(m,                                                      77),                                                                              HCl.salt                                                                              302   n-BuOH                                                                             120° C.               4.23(s, 1H), 4.5-4.8(m, 1H), 4.95-5.4(m, 2H),                                                               166-169° C.                                                                    238   K.sub.2 CO.sub.3                                                                   14 h                         5.8-6.2(m, 1H), 6.23(d, 1H, J=3.5Hz), 6.56(d, 1H,                                                           i-PrOHz),                                                                             206        B                            7.1-6.9(m, 4H), 7.5-7.2(m, 4H)                                         29 135 3.63(s, 6H), 3.9-4.25(m, 12H), 4.7(br-t, 2H, J=6Hz),                                                    87  HCl.salt                                                                              --    n-BuOH                                                                             100° C.               4.95-5.4(m, 4H), 5.8-6.3(m, 2H), 6.34(d, 2H, J=3.7Hz),                                                      170-175° C.                                                                          K.sub.2 CO.sub.3                                                                   24 h                         6.61(d, 2H, J=3.7Hz)          (dec)              B                                                          --                                       30 136 2.46(t-like, 4H, J=5Hz), 3.09(s, 3H), 3.61(s, 3H),                                                      58  HCl.salt                                                                              302   n-BuOH                                                                             120° C.               3.87(t-like, 4H, J=5Hz), 4.15-4.4(m, 3H), 4.9-5.3(m,                                                        155-161° C.                                                                    241   K.sub.2 CO.sub.3                                                                   8 h                          5.6-6.1(m, 1H), 6.21(d, 1H, J=3.6Hz), 6.55(d, 1H,                                                           i-PrOHz),                                                                             206        B                            6.8-7.6(m, 8H)                                                         31 137 2.45(t-like, 4H, J=5Hz), 3.60(s, 3H),                                                                   54  --      --    DMF  100° C.               3.85(t-like, 4H, J=5Hz), 4.15-4.3(m, 5H), 5.0-5.3(m,                                                                      K.sub.2 CO.sub.3                                                                   5 h                          5.7-6.1(m, 2H), 6.21(d, 1H, J=4Hz), 6.55(d, 1H, J=4Hz),                                                                        B                            7.1-6.9(m, 4H), 7.5-7.2(m, 4H)                                         32 138 1.4-2.3(m, 4H), 2.08(s, 3H), 2.38(s, 3H),                                                               30  fumarate                                                                              --    n-BuOH                                                                             120° C.               3.5-3.85(m, 2H), 3.73(s, 3H), 4.0-4.4(m, 2H),                                                               --            K.sub.2 CO.sub.3                                                                   4 h                          4.66(d, 2H), J=5.3Hz), 4.8-5.35(m, 3H), 5.7-6.2(m,                                                          EtOH               B                            6.43(d, 1H, J=3.6Hz), 6.89(d, 1H, J=3.6)                               33 139 2.03(t-like, 4H, J=5Hz), 3.5-3.3(m, 9H), 3.74(s,                                                        60),                                                                              --      --    n-BuOH                                                                             120° C.               5.8(br-s, 1H), 6.17(d, 1H, J=3.6Hz), 6.51(d, 1H,                                                                          K.sub.2 CO.sub.3                                                                   5 h                          6.72(d, 2H, J=9Hz), 7.3-6.9(m, 17H)              B                     34 140 0.90(t, 3H, J=7Hz), 0.95(t, 3H, J=7Hz), 1.4-2.04(m,                                                     94),                                                                              HCl.salt                                                                              --    n-BuOH                                                                             120° C.               2.46(t-like, 4H, J=5Hz), 3.2-3.5(m, 2H), 3.74-4.1(m,                                                        181-189° C.                                                                          K.sub.2 CO.sub.3                                                                   24 h                         4.23(s, 1H), 4.7(br-s, 1H), 6.22(d, 1H, J=4Hz),                                                             EtOH               B                            6.59(d, 1H, J=4Hz), 6.8-7.15(m, 4H), 7.2-7.5(m, 4H)                    35 141 0.89(t, 3H, J=7Hz), 1.55-2.05(m, 2H),                                                                   64  HCl.salt                                                                              --    DMF  100° C.               2.46(t-like, 4H, J=5Hz), 3.75-4.15(m, 8H), 4.23(s,                                                          129-131° C.                                                                          K.sub.2 CO.sub.3                                                                   14 h                         4.65(br-t, 1H), 4.95-5.4(m, 2H), 5.75-6.2(m, 1H),                                                           i-PrOH             B                            6.23(d, 1H, J=4Hz), 6.60(d, 1H, J=4Hz), 6.85-7.15(m, 4H),                     7.2-7.5(m, 4H)                                                         36 142 0.2-0.7(m, 4H), 0.9-1.4(m, 1H), 2.46(t-like, 4H,                                                        655Hz),                                                                           HCl.salt                                                                              --    DMF  100° C.               3.7-4.15(m, 8H), 4.23(s, 1H), 4.45-4.8(br-s, 1H),                                                           165-169° C.                                                                          K.sub.2 CO.sub.3                                                                   14 h                         4.95-5.4(m, 2H), 5.75-6.2(m, 1H), 6.25(d, 1H, J=4Hz),                                                       EtOH               B                            6.73(d, 1H, J=4Hz), 6.85-7.15(m, 4H), 7.2-7.5(m, 4H)                   37 143 2.46(t-like, 4H, J=5Hz), 3.75-4.1(m, 6H), 4.24(s,                                                       97),                                                                              HCl.salt                                                                              --    DMF  100° C.               4.5-4.7(m, 3H), 4.95-5.35(m, 4H), 5.7-6.2(m, 2H),                                                           167-173° C.                                                                          --   B                            6.26(d, 1H, J=4Hz), 6.59(d, 1H, J=4Hz), 6.9-7.1(m,                                                          i-PrOH                                          7.2-7.5(m, 4H)                                                         38 145 2.46(t-like, 4H, J=5Hz), 3.86(t-like, 4H, J=5Hz),                                                       73  --      --    DMF  50° C.                4.1-4.3(m, 5H), 4.6-4.75(m, 2H), 4.95-5.3(m, 6H),                                                                         K.sub.2 CO.sub.3                                                                   10 h                         5.7-6.2(m, 3H), 6.23(d, 1H, J=4Hz), 6.58(d, 1H, J=4Hz),                                                                        B                            6.85-7.15(m, 4H), 7.2-7.5(m, 4H)                                       39 146 2.46(t-like, 4H, J=5Hz), 3.88(t-like, 4H, J=5Hz),                                                       62  HCl.salt                                                                              304   DMF  100° C.               4.03(m, 2H), 4.23(s, 1H), 4.7(bs-s, 1H), 4.9-5.3(m,                                                         187-190° C.                                                                    239   K.sub.2 CO.sub.3                                                                   6 h                          5.21(s, 2H), 5.7-6.2(m, 1H), 6.25(d, 1H, J=3.6Hz)                                                           EtOH    209        B                            6.55(d, 1H, J=3.6Hz), 6.8-7.5(m, 13H)                                  40 148 0.1-0.5(m, 4H), 1.0(m, br, 1H), 1.60(d, 3H, J=7Hz),                                                     95  HCl.salt                                                                              297   n-BuOH                                                                             130° C.               3.23(2H, dd, J=7Hz, 7Hz), 3.60(3Hz), 4.7(br, 1H),                                                           118-119° C.                                                                    235   K.sub.2 CO.sub.3                                                                   20 h                         5.0(br, 1H), 5.4(m, 1H), 6.11(d, 1H, J=3.5Hz),                                                              acetone-                                                                              206        A                            6.52(d, 1H, J=3.5Hz), 7.2-7.4(m, 5H)                                                                        diethylether                             41 149 3.62(s, 3H), 4.09(t-2H, J=5.5Hz), 4.5-5.2(br, 3H)                                                       100 HCl.salt                                                                              302   aq.  110° C.               5.0-5.4(m, 2H), 5.8-6.3(m, 1H), 6.16(d, 1H, J=3.5Hz),                                                       215-223° C.                                                                    268   ammonia                                                                            15 h                         6.58(d, 1H, J=3.5Hz)          (dec.)  235   --   A                                                          i-PrOH/ 207                                                                   (i-Pr).sub.2 O                           42 150 1.1-2.2(m, 10H), 3.62(s, 3H), 3.9-4.2(m, 3H),                                                           92  HCl.salt                                                                              296   --   120° C.               4.4-4.8(m, 2H), 5.0-5.4(m, 2H), 5.7-6.3(m, 1H),                                                             187-189° C.                                                                    235   K.sub.2 CO.sub.3                                                                   19 h                         6.14(d, 1H, J=3.4Hz), 6.56(d, 1H, J=3.4Hz)                                                                  i-PrOH             B                     43 151 3.63(s, 3H), 4.0-4.3(m, 4H), 4.7(br, 2H), 4.95-5.4(m,                                                   76),                                                                              --      --    n-BuOH                                                                             100° C.               5.8-6.3(m, 2H), 6.18(d, 1H, J=3.5Hz), 6.59(d, 1H,                                                                         --3.5Hz)                                                                           18 h                                                                          B                     44 152 2.28(s, 6H), 2.55(t, 2H, J=5.7Hz), 3.5-3.7(m, 4H),                                                      93  HCl.salt                                                                              297   --   110° C.               4.0-4.2(m, 2H), 4.7(br-s, 1H), 4.9-5.4(m, 2H),                                                              199-212° C.                                                                    234   K.sub.2 CO.sub.3                                                                   15 h                         5.4(br-s, 1H), 5.8-6.3(m, 1H), 6.21(d, 1H, J=3.5Hz),                                                        (dec.)             B                            6.56(d, 1H, J=3.5Hz)          EtOH                                     45 153 1.4-1.8(m, 4H), 2.3-2.7(m, 6H), 3.62(s, 3H),                                                            93  HCl.salt                                                                              297   --   130° C.               3.5-3.7(m, 2H), 4.10(m, 2H), 4.6(m, 1H), 5.0-5.4(m,                                                         210-220° C.                                                                    234   K.sub.2 CO.sub.3                                                                   3 h                          5.8-6.2(m, 1H), 6.21(d, 1H, J=3.5Hz), 6.56(d, 1H,                                                           (dec.)z)           B                                                          EtOH                                     46 154 2.4-2.7(m, 6H), 3.63(s, 3H), 3.5-3.8(m, 6H),                                                            60  HCl.salt                                                                              296   --   130° C.               4.10(br-t, 2H, J=6Hz), 4.8-5.5(m, 4H), 5.6-6.2(m,                                                           205-212° C.                                                                    234   K.sub.2 CO.sub.3                                                                   B                            6.20(d, 1H, J=3.5Hz), 6.58(d, 1H, J=3.5Hz)                                                              > (dec.)                                                                          EtOH                                     47 155 3.63(s, 3H), 4.10(t, 2H, J=5.5Hz), 4.6-4.85(m, 3H),                                                     94  HCl.salt                                                                              295   --   130° C.               4.9-5.4(m, 3H), 5.7-6.3(m, 1H), 6.12(d, 1H, J=3.5Hz),                                                       174-178° C.                                                                    235   K.sub.2 CO.sub.3                                                                   5 h                          6.56(d, 1H, J=3.5Hz), 7.2-7.5(m, 5H)                                                                        acetone 208        B                     48 160 1.82(s, 6H), 3.58(s, 3H), 3.67(t, 2H, J=5.3Hz),                                                         91  HCl.salt                                                                              297   n-BuOH                                                                             180° C.               4.5(br-t, 1H, J=5.5Hz), 4.85-5.2(m, 2H), 5.5-5.95(m,                                                        181-200° C.                                                                    269   K.sub.2 CO.sub.3                                                                   16 h                         4.06(d, 1H, J=3.5Hz), 6.53(d, 1H, J=3.5Hz), 7.1-7.6(m,                                                      acetone 234        A                                                                  207                              49 161 1.75(d, 3H, J=6.6Hz), 3.59(s, 3H), 4.01(br-t, 2H,                                                       705.2Hz),                                                                         HCl.salt                                                                              294   --   150° C.               4.7(br-t, 1H, J=5.2Hz), 4.9-5.35(m, 3H), 5.7-6.2(m,                                                         135-140° C.                                                                    223   K.sub.2 CO.sub.3                                                                   6 h                          6.0(d, 1H, J=3.5Hz), 6.2(t, 1H, J=7Hz), 6.48(d, 1H,                                                         i-PrOHz),          B                            7.3-8.3(m, 7H)                                                         50 162 1.7-2.3(m, 4H), 2.83(br-t, 2H, J=6Hz), 3.64(s, 3H),                                                     79  HCl.salt                                                                              297   --   130° C.               4.11(br-t, 2H, J=6Hz), 4.7(br-t, 1H, J=6Hz), 4.8-5.4(m,                                                     196-200° C.                                                                    235   K.sub.2 CO.sub.3                                                                   6 h                          5.5(m, 1H), 5.8-6.4(m, 1H), 6.09(d, 1H, J=3.6Hz),                                                           (dec.)  207        B                            6.56(d, 1H, J=3.6Hz), 7.0-7.5(m, 4H)                                                                        i-PrOH                                   51 163 3.60(s, 3H), 3.96(t, 3H, J=6Hz), 4.65(br-t, 1H, J=6Hz),                                                 45  HCl.salt                                                                              298   --   150° C.               4.9-5.35(m, 3H), 5.65-6.1(m, 1H), 6.12(d, 1H, J=3.5Hz),                                                     183-185° C.                                                                    236   K.sub.2 CO.sub.3                                                                   27 h                         6.50(s, 1H), 6.54(d, 1H, J=3.5Hz), 7.2-7.4(m, 10H)                                                          i-PrOH  208        B                     52 164 2.95(t, 2H, J=6.8Hz), 3.62(s, 3H), 3.6-3.95(m, 2H),                                                     100 HCl.salt                                                                              295   --   130° C.               4.0-4.2(m, 2H), 4.5-4.9(m, 2H), 4.95-5.4(m, 2H),                                                            152-153° C.                                                                    234   K.sub.2 CO.sub.3                                                                   1.5 h                        5.8-6.3(m, 1H), 6.09(d, 1H, J=3.5Hz), 6.55(d, 1H,                                                           i-PrOHz),                                                                             207        B                            7.2-7.4(m, 5H)                                                         53 165 3.29(s, 6H), 3.62(s, 3H), 4.0-4.2(m, 2H), 4.6(br-s,                                                     50),                                                                              HCl.salt                                                                              299   n-BuOH                                                                             120° C.               5.0-5.4(m, 2H), 5.8-6.3(m, 1H), 6.38(d, 1H, J=3.5Hz),                                                       175-180° C.                                                                    236   K.sub.2 CO.sub.3                                                                   14 h                         6.56(d, 1H, J=3.5Hz)          EtOH    202        A                     54 166 3.26(s, 3H), 3.62(s, 3H), 4.07(t-like, 2H, J=6Hz),                                                      99  Fumarate                                                                              --    n-BuOH                                                                             100° C.               4.7(br, 1H), 4.96(s, 2H), 4.9-5.4(m, 2H), 5.75-6.3(m,                                                       163-164° C.                                                                          --   B                            6.26(d, 1H, J=3.6Hz), 6.53(d, 1H, J=3.6Hz), 7.2-7.4(m,                                                      EtOH                                     55 167 2.97(dd, 2H, J=7.5, J=9.9Hz), 3.22(s, 3H), 3.63(s,                                                      74),                                                                              HCl.salt                                                                              299   --   140° C.               3.88(dd, 2H, J=7.5, J=9.9Hz), 4.1(m, 2H), 4.6(br-t, 1H,                                                     177-183° C.                                                                    236   K.sub.2 CO.sub.3                                                                   14 h                         Hz), 4.95-5.4(m, 2H), 5.8-6.3(m, 1H), 6.35(d, 1H,                                                           i-PrOHz),                                                                             207        B                            6.57(d, 1H, J=3.5Hz), 7.1-7.4(m, 5H)                                   56 168 1.09(t, 3H, J=7Hz), 1.63(d, 3H, J=7Hz), 3.3-3.7(m,                                                      49),                                                                              --      --    --   150° C.               3.62(s, 3H), 4.07(dd, 2H, J=5.5Hz, 5.5Hz), 4.7(br-t,                                                                      K.sub.2 CO.sub.3                                                                   40 h                         1H), 5.0-5.3(m, 2H), 5.8-6.2(m, 1H), 6.25(d, 1H,                                                                          LiI.5Hz),                                                                          A                            6.50(d, 1H, J=7Hz), 6.56(d, 1H, J=3.5Hz), 7.2-7.4(m, 5H)               57 169 1.60(3H, d, J=7Hz), 1.75(3Hz), 3.59(s, 3H), 4.7(s, br,                                                  80),                                                                              HCl.salt                                                                              296   n-BuOH                                                                             130° C.               3.97(d, 2H, J=6Hz), 4.8(s, 1H), 4.9(s, 1H), 5.1(s, br,                                                      160-164° C.                                                                    235   K.sub.2 CO.sub.3                                                                   15 h                         5.4(m, 1H), 6.11(d, 1H, J=3.5Hz), 6.52(d, 1H, J=3.5Hz),                                                     acetone 206        A                            7.2-7.4(m, 5H)                                                         58 171 3.29(s, 6H), 4.07(t-like, 2H, J=6Hz), 4.64(d, 2H,                                                       745.5Hz),                                                                         HCl.salt                                                                              299   n-BuOH                                                                             120° C.               4.9-5.4(m, 4H), 5.7-6.2(m, 2H), 6.41(d, 1H, J=3.5Hz),                                                       110-111° C.                                                                    237   K.sub.2 CO.sub.3                                                                   16 h                         6.59(d, 1H, J=3.5Hz)          EtOH    207        B                     59 172 3.63(s, 3H), 4.12(t-like, 2H, J=5.6Hz),                                                                 77  HCl.salt                                                                              235.0 n-BuOH                                                                             110° C.               4.76(d, 2H, J=5.6Hz), 4.76(br-s, 1H), 5.08(br-s,                                                            158-160° C.                                                                          K.sub.2 CO.sub.3                                                                   9 h                          5.10(dd, 1H, J=1.7, 10.2Hz),  i-PrOH             B                            5.26(dd, 1H, J=1.7, 17.2Hz), 5.94-6.08(br-s, 1H),                             6.26-6.33(m, 1H), 6.36(dd, 2H, J=3.6, 114.8Hz),                               7.37(d, 1H, J=1.7Hz)                                                   60 173 2.00(quint, 2h, J=7.3Hz), 2.75(t, 2H, J=7.6Hz),                                                         58  maleate 222.8 n-BuOH                                                                             80° C.                3.49-3.64(m, 2H), 3.62(s, 3H), 4.09(t-      K.sub.2 CO.sub.3                                                                   40 h                         like, 2H, J=5.6Hz), 4.68(br-s, 1H), 4.79(br-s, 1H),                                                                            B                            5.09(dd, 1H, J=1.3, 10.2Hz),                                                  5.25(dd, 1H, J=1.7, 17.2Hz), 5.93-6.08(m, 2H), 6.28-                          6.30(m, 1H), 6.35(dd, 2H, J=3.6, 119.8Hz),                                    7.32(d, 1H), J=1.7Hz)                                                  61 174 3.6(s, 3H), 4.1(t-like, J=6Hz), 4.7(br-s, 1H), 4.8-                                                     78  HCl.salt                                                                              230.0 n-BuOH                                                                             100° C.               5.4(m, 5H), 5.8-6.0(m, 1H), 6.3(dd, 2H, J=4, 39Hz),                                                                       K.sub.2 CO.sub.3                                                                   19 h                         6.4-7.3(m, 3H)                                   B                     62 175 2.90(t, 2H, J=7.0Hz), 3.63(s,3H), 3.63-3.80(m, 2H),                                                     64  HCl.salt                                                                              228.2 n-BuOH                                                                             100° C.               3.80(s, 3H), 4.12(t-like, 2H, J=5.6Hz), 4.70(br-                                                                          K.sub.2 CO.sub.3                                                                   15 h                         s, 1H), 4.74(br-s, 1H), 5.10(dd, 1H, J=1.3, 10.2Hz),                                                                           B                            5.27(dd, 1H, J=1.7, 17.2Hz), 5.95-6.10(m, 2H),                                6.56(d, 1H, J=3.3Hz), 7.00(dd, 4H, J=8.58, 79.2Hz)                     63 176 1.28(d, 6H, J=6.6Hz), 3.63(s, 3H), 4.10(t-                                                              74  HCl.salt                                                                              228.6 n-BuOH                                                                             120° C.               like, 2H, J=5.6Hz), 4.30-4.40(m, 1H), 4.60-                                                                 190-199° C.                                                                          K.sub.2 CO.sub.3                                                                   15 h                         4.73(br-s, 2H), 5.09(dd, 1H, J=1.7, 10.2Hz),                                                                i-PrOH             A                            5.25(dd, 1H, J=1.7, 17.2Hz), 5.93-6.08(m, 1H),                                6.16(d, 1H, J=3.6Hz), 6.57(d, 1H, J=3.3Hz)                             64 177 0.98(d, 6H, J=6.6Hz), 1.94(hept, 1H, J=6.6Hz),                                                          65  HCl.salt                                                                              229.0 n-BuOH                                                                             120° C.               3.37(t-like, 2H, J=6.6Hz), 3.63(s, 3H), 4.10(t-                                                             145-148° C.                                                                          K.sub.2 CO.sub.3                                                                   2.5 h                        like, 2H, J=5.6Hz), 4.69(br-s, 1H), 4.86(br-s, 1H),                                                         i-PrOH             A                            5.09(dd, 1H, J=1.7, 10.2Hz), 5.25(dd, 1H, J=1.7,                              17.2Hz) 5.93-6.08(m, 1H), 6.17(d, 1H, J=3.6Hz),                               6.57(d, 1H, J=3.6Hz)                                                   65 178 1.52(s, 9H), 3.61(s, 3H), 4.10(t-like, 2H, J=5.6Hz),                                                    4   HCl.salt                                                                              228.4 n-BuOH                                                                             120° C.               4.60(br-s, 1H), 5.19(dd, 1H, J=1.7, 17.2Hz), 6.04-                                                                        K.sub.2 CO.sub.3                                                                   16 h                         6.16(m, 1H), 6.09(d, 1H, J=3.3Hz),               A                            6.54(d, 1H, J=3.6Hz)                                                   66 179 1.59-1.71(m, 1H), 1.85-2.06(m, 3H), 3.46-                                                               95  HCl.salt                                                                              228.4 n-BuOH                                                                             120° C.               3.55(m, 1H), 3.62(s, 3H), 3.76-3.95(m, 3H), 4.07-                                                                         K.sub.2 CO.sub.3                                                                   2.5 h                        4.16(m, 3H), 4.71(br-s, 1H), 5.06-5.29(m, 3H), 5.93-                                                                           B                            6.07(m, 1H), 6.17(d, 1H, J=3.3Hz),                                            6.56(d, 1H, J=3.6Hz)                                                   67 180 1.60-1.69(m, 2H), 1.93-2.05(m, 2H),                                                                     29  HCl.salt                                                                              234.2 n-BuOH                                                                             100° C.               3.39(d, 3H, J=0.9Hz), 3.45-3.58(m, 3H), 3.63(s, 3H),                                                                      K.sub.2 CO.sub.3                                                                   6 h.                         4.09(t-like, 2H, J=5.6Hz), 4.23-4.32(m, 2H),     B                            4.65(br-s, 1H), 5.08(dd, 1H, J=1.3H, 10.2Hz),                                 5.25(dd, 1H, J=1.3, 17.2Hz), 5.93-6.07(m, 1H),                                6.46(dd, 2H, J=3.6, 76.5Hz)                                            68 181 1.20(t, 6H, J=6.9Hz), 3.51(q, 4H, J=6.9Hz)                                                              59  HCl.salt                                                                              235.2 n-BuOH                                                                             80° C.                3.62(s, 3H), 3.69(t, 4H, J=6.3Hz),          K.sub.2 CO.sub.3                                                                   25 h                         3.90(t, 4H, J=6.3Hz, 4.06(t-like, 2H, J=6Hz),    B                            4.64(br-s, 1H), 5.07(dd, 1H, J=1.3, 10.2Hz),                                  5.23(dd, 1H, J=1, 7, 17.2Hz), 5.92-6.06(m, 1H),                               6.32(dd, 2H, J=3.6, 79.2Hz)                                            69 182 1.27(3H, d, J=6.9Hz), 1.49-1.85(6H, m),                                                                 82  HCl.salt                                                                              299   --   120° C.               3.19(1H, dt, J=12.9&2.6Hz), 3.63(3H, s), 4.05-                                                              --      235   K.sub.2 CO.sub.3                                                                   16 h                         4.16(3H, m), 4.60-4.65(1H, m), 4.98-5.06(1H, m),                                                            EtOH          --   A                            5.08(1H, dd, J=10.2&1.3Hz),                                                   5.25(1H, dd, J=17.2&1.7Hz), 5.93-6.07(1H, m),                                 6.31(1H, d, J=3.6Hz), 6.58(1H, d, J=3.6Hz)                             70 183 1.30(6H, d, J=6.9Hz), 1.51-2.04(6H, m), 3.62(3H,                                                        6), HCl.salt                                                                              299   --   160° C.               4.07(2H, t, J=5.6Hz), 4.77(1H, br), 5.05(1H, br),                                                           --      236   K.sub.2 CO.sub.3                                                                   48 h                         5.07(1H, dd, J=10.2&1.0Hz),   --            LiI  A                            5.23(1H, dd, J=17.3&1.2Hz), 5.93-6.07(1H, m),                                 6.29(1H, d, J=3.6Hz), 6.57(1H, d, J=3.6Hz)                             71 184 3.39(6H, s), 3.49-3.55(2H, m), 3.62(3H, s), 3.62-                                                       23  HCl.salt                                                                              --    n-BuOH                                                                             120° C.               3.67(2H, m), 4.06-4.13(2H, m), 4.51-4.62(1H, m),                                                            --            K.sub.2 CO.sub.3                                                                   48 h                         4.71-4.76(1H, m), 5.08(1H, dd, J=10.2&1.3Hz), 5.11-                                                         --            --   A                            5.20(1H, m), 5.24(1H, dd, J=17.1&1.7Hz), 5.92-                                6.04(1H, m), 6.17(1H, d, J=3.3Hz),                                            6.57(1H, d, J=3.6Hz)                                                   72 185 1.55-1.75(4H, m), 1.75-2.00(4H, m), 3.33(3H, s),                                                        35  HCl.salt                                                                              296   n-BuOH                                                                             120° C.               3.35-3.45(1H, br), 3.61(3H, s), 4.05-4.15(3H, m),                                                           --      277   K.sub.2 CO.sub.3                                                                   28 h                         4.65-4.75(2H, br), 5.08(1H, dd, J=10&1Hz),                                                                  --      234   LiI  A                            5.25(1H, dd, J=17&1Hz), 5.93-6.07(1H, m),                                     6.13(1H, d, J=3.3Hz), 6.56(1H, d, J=3.3Hz)                             73 186 1.17-1.46(4H, m), 2.08-2.22(4H, m),                                                                     47  HCl.salt                                                                              295   n-BuOH                                                                             140° C.               3.17(1H, tt, J=10.2&4.0Hz), 3.36(3H, s), 3.62(3H,                                                           202-3° C.                                                                      232   K.sub.2 CO.sub.3                                                                   36 h                         3.97-4.11(3H, m), 4.63(1H, d, J=7.59Hz),                                                                    CH.sub.3 CN   LiI  A                            4.70(1H, t, J=5.94Hz), 5.08(1H, dq, J=10.2&1.3Hz),                            5.24(1H, dq, J=17.2&1.7Hz), 5.92-6.07(1H, m),                                 6.14(1H, d, J=3.3Hz), 6.57(1H, d, J=3.3Hz)                             74 187 1.20-1.32(2H, m), 1.22(3H, t, J=6.9Hz),                                                                 70  H.sub.2 SO.sub.4.salt                                                                 293   n-BuOH                                                                             120° C.               1.45(2H, dq, J=12.9&3.0Hz), 2.08-2.22(4H, m),                                                               170-2° C.                                                                      270   K.sub.2 CO.sub.3                                                                   38 h                         3.32(1H, tt, J=10.2&4.0Hz), 3.54(2H, q, J=6.9Hz),                                                           CH.sub.3 CN                                                                           230   LiI  A                            3.58-3.68(4H, m), 3.62(3H, s), 3.95-4.10(3H, m),                              4.61-4.72(2H, m), 5.09(1H, dq, J=10.2&1.3Hz),                                 5.25(1H, dq, 17.2&1.7Hz), 5.93-6.07(1H, m),                                   6.13(1H, q, J=3.3Hz), 6.57(1H, d, J=3.6Hz)                             75 188 1.53-1.68(2H, m), 2.06-2.11(2H, m), 3.52-                                                               30  HCl.salt                                                                              294   n-BuOH                                                                             160° C.               3.60(2H, m), 3.65(3H, s), 4.00-4.11(4H, m),                                                                 --      232   K.sub.2 CO.sub.3                                                                   16 h                         4.29(1H, br), 4.61-4.75(2H, m),                                                                             --            --   A                            5.12(1H, dd, J=10.2&1.7Hz),                                                   5.27(1H, dd, J=17.2&1.7Hz), 5.91-6.03(1H, m),                                 6.18(1H, d, J=3.6Hz), 6.62(1H, d, J=3.6Hz)                             76 189 1.32-1.47(2H, m), 1.53-1.68(2H, m), 1.84-                                                               63  HCl.salt                                                                              297   n-BuOH                                                                             120° C.               1.89(2H, m), 2.16-2.21(2H, m), 3.08-3.19(1H, m),                                                            --      235   K.sub.2 CO.sub.3                                                                   48 h                         3.14(3H, s), 3.38(3H, s), 3.62(3H, s), 4.05-                                                                EtOH          LiI  A                            4.11(2H, m), 4.16-4.73(2H, m),                                                5.08(1H, dq, J=10.2&1.7Hz),                                                   5.24(1H, dq, J=17.2&1.7Hz), 5.93-6.07(1H, m),                                 6.33(1H, d, J=3.6Hz), 6.57(1H, d, J=3.3Hz)                             77 190 3.63(3H, s), 3.76(6H, s), 3.90-3.97(2H, m), 4.08-                                                       86  HCl.salt                                                                              293   n-BuOH                                                                             120° C.               4.17(4H, m), 4.77-4.82(1H, br),                                                                             --      270   K.sub.2 CO.sub.3                                                                   22 h                         5.10(1H, dd, J=10.2&1.3Hz), 5.11(1H, br),                                                                   H.sub.2 O                                                                             228   --   A                            5.26(1H, dd, J=17.2&1.7Hz), 5.94-6.06(1H, m), 6.09-                           6.10(1H, m), 6.16-6.17(3H, m), 6.58(1H, d, J=3.6Hz)                    __________________________________________________________________________     (*A: Autoclave B: Normal pressure and open system)                            Wherein, iPrOH: isopropylalcohol; nBuOH: Nbutylalchol; EtOH: ethylalcohol     (iPr).sub.2 O: diisopropylether                                          

Example 78 Effect on Partial Pressure Value of Gases in Arterial Blood(Injection system)

<Method A>

Male Wister strain rats (body weight about 300 g) were anesthetizedintra-peritoneally with urethane, and a cannula was inserted into therespiratory tract and the femoral artery, respectively. A suspension(30-100 μm, 10 mg/ml) of carbon powder in a corn oil was intratrachealyinjected to induce a hypoxemia state (PaO₂ ; 50-60 mmHg). A compound inaccordance with the present invention was continuously intravenouslyinjected into these hypoxemia model animals (0.1 mg/kg/min., 10 min.),and then a partial pressure value of gases (PaO₂, PaCO₂) in arterialblood was immediately determined.

<Method B>

Male Wister strain rats (body about 300 g) were anesthetized withhalothane inhalant, and then 2.0% acetic acid was intratrachealyinjected at 0.6 ml/kg to induce a respiratory insufficiency. The animalswere intra-peritoneally anesthetized with urethane-α-chloralose, and acannula was inserted into the femoral artery. After the hypoxemic state(PaO₂ : 60-70 mmHg) was observed a compound in accordance with thepresent invention (test substance) was continuously intravenouslyinjected into these hypoxemia model animals (0.1 mg/kg/min., 10 min.),and then a partial pressure value of gases (PaO₂, PaCO₂) in arterialblood was immediately determined.

The results are as shown in Table 1.

    ______________________________________                                        Activity for Increasing PaO.sub.2 and                                         Decreasing PaCO.sub.2 by Intravenous Injection                                                  Activity for                                                                              Activity for                                                      Increasing PaO.sub.2                                                                      Decreasing PaCO.sub.2                           Test              .increment.PaO.sub.2                                                                      .increment.PaCO.sub.2                           Compound                                                                              Method    (mmHg)      (mmHg)                                          ______________________________________                                        119     A         +7.1        -2.6                                            124     B         +5.7        -4.0                                            133     A         +6.9        -0.6                                            143     A         +5.0        +1.1                                            150     B         +18.4       -18.6                                           156     B         +19.7       -9.1                                            162     B         +18.1       -17.2                                           164     B         +15.4       -19.2                                           165     B         +7.9        +1.1                                            167     B         +11.3       -6.6                                            172     B         +12.3       -2.8                                            173     B         +12.0       -13.1                                           174     B         +5.8        -2.9                                            175     B         +15.2       -13.1                                           176     B         +22.2       -14.8                                           178     B         +16.4       -16.4                                           179     B         +8.5        +2.4                                            180     B         +6.5        -0.5                                            181     B         +6.4        +1.2                                            183     B         +10.7       -4.6                                            184     B         +7.8        -0.7                                            185     B         +11.7       -6.0                                            186     B         +12.3       -15.4                                           187     B         +13.7       -14.7                                           189     B         +7.3        -6.0                                            ______________________________________                                         (Indication of activity)                                                      .increment.PaO.sub.2 = (PaO.sub.2 after administration  PaO.sub.2 before      administration) for test compound                                             .increment.PaCO.sub.2 = (PaCO.sub.2 after administration  PaCO.sub.2          before administration) for test compound                                 

Example 79 Effect on Partial Pressure Value of Gases in Arterial Blood(Oral Administration System)

Method A

Male Wistar strain rats (body weight about 250 g) fasted overnight wereanesthetized with halothane inhalant, and a cannula then inserted intothe femoral artery. After the animals recovered from the anesthesia,they were again anesthetized with halothane inhalant, and then 2.0%acetic acid was intratrachealy injected at 0.8 ml/kg to induce ahypoxemia state. After the hypoxemic state (PaO₂ :60-80 mmHg) wasobserved over about 60 min., a compound in accordance with the presentinvention (test substance, 10 or 30 mg/kg) was orally administered tothe animals. Then 60 min. after the administration, the partial pressurevalue of gases (PaO₂, PaCO₂) in arterial blood was determined.

Method B

Male wistar strain rats (body weight about 350 g) were anesthetized withhalothane inhalant, and then 2.0% acetic acid were intratrachealyinjected at 0.6 ml/kg body to induce a hypoxemia state. In 3 days afterinjection with 2.0% acetic acid, rats fasted overnight were anesthetizedwith halothane inhalant, and a cannula inserted into the femoral artery.After these hypoxemia animals (PaO₂ : 60-80 mmHg) were recovered fromthe anesthesia, a compound in accordance with the present invention(test substance, 10 or 30 mg/kg) was orally administered to the animals.At 60 min. after the administration, the partial pressure value of gases(PaO₂, PaCO₂) in arterial blood was determined.

The results are aS shown in Table 2.

    ______________________________________                                        Activity for Increasing PaO.sub.2 and                                         Decreasing PaCO.sub.2 by Oral Administration                                                          Activity for                                                                            Activity for                                                        Increasing PaO.sub.2                                                                    Decreasing PaCO.sub.2                       Test            Dose    .increment.PaO.sub.2                                                                    .increment.PaCO.sub.2                       Compound                                                                              Method  (mg/kg) (mmHg)    (mmHg)                                      ______________________________________                                        124     B       30      +8.0      -2.5                                        156     A       30      +7.8      -8.1                                        165     A       30      +8.5      -3.4                                        173     A       10      +4.2      -3.7                                        176     B       10      +11.6     -5.4                                        178     B       10      +17.0     -6.6                                        182     B       30      +3.3      -2.2                                        186     B       10      +14.9     -5.3                                        187     B       10      +16.0     +6.9                                        ______________________________________                                         (Indication of activity)                                                      .increment.PaO.sub.2 = (PaO.sub.2 after administration  PaO.sub.2 before      administration) for test compound                                             .increment.PaCO.sub.2 = (PaCO.sub.2 after administration  PaCO.sub.2          before administration) for test compound                                 

Example 80 Preparation of Tablet

A tablet containing 30 mg of the compound prepared in Example 1 wasprepared as follows:

Compound prepared in Ex. 1 30 mg

Lactose 87 mg

Starch 30 mg

Magnesium stearate 3 mg

Example 72 Preparation of Injection

A solution for injection containing 0.3 mg, based on ml of the solution,of the compound prepared in Example 1 was prepared according to thefollowing formulation.

Compound prepared in Ex. 1 30 mg

Sodium chloride 900 mg

Distilled water for injection 100 ml

INDUSTRIAL APPLICABILITY

The compounds in accordance with the present invention, andpharmaceutical preparations thereof, are particularly useful for thetreatment of hypoxemia associated with respiratory diseases, andfurther, an effective process for producing same is provided.

We claim:
 1. A pyrrolo[2,3-d]pyrimidine derivative represented by thegeneral formula I: ##STR218## wherein R¹ represents a hydrogen atom, oran unsubstituted or substituted alkyl, alkenyl or arylalkyl group;R² andR³ independently of each other represent a hydrogen atom, or anunsubstituted or substituted alkyl, alkenyl, arylalkyl or alkycarbonylgroup; or R² and R³ are optionally taken together with the adjacentnitrogen atom to form an unsubstituted saturated 5- to 7- member ring,which may be constructed with one or two hereto atoms selected from thegroup consisting of N, O and S; R⁴ and R⁵ independently of each otherrepresent a hydrogen atom, halogen atom, or an unsubstituted orsubstituted alkyl group; Y is a linking group bonded to the pyrimidinering via a nitrogen atom therein of the formula: ##STR219## wherein Grepresents a hydrogen atom or an alkyl group; Z represents a groupbonded to a carbon or nitrogen atom in the linking group, and is ahydrogen atom, an unsubstituted or substituted alkyl, alkenyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, alkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, arylalkylcarbonyl, heteroarylalkylcarbonyl,alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy,arylalkylcarbonyloxy, heteroarylalkylcarbonyl, alkyloxy oralkyloxyimino-alkyl group; or mono- or di-alkylamino, mono- ordi-alkylcarbonylamino or N-alkyl-N-alkylcarbonylamino group; orrepresents a group bonded to a carbon atom in the linking group, and isa carboxyl or hydroxyl group; or Y and Z are taken together to formmorpholino or thiomorpholino group; each substituent in said substitutedgroup is substituted at a chain or cyclic moiety of the alkyl, alkenyl,arylalkyl, heteroarylalkyl, aryl, or heteroaryl moiety, respectively,and represents an alkyl, alkyloxy, alkylcarbonyl, alkylcarbonyloxy,hydroxy, mono- or di-alkylamino, amino, nitro, cyano group, or a halogenatom, wherein the heteroaryl groups represent respectively a groupselected from the group consisting of pyrrolyl, furyl, thienyl, andpyridyl, with a proviso that R² and R³ do not represent a hydrogen atomat the same time, and that when R¹ represents a hydrogen atom, thecombinations wherein one of R² and R³ represents a hydrogen atom andanother represents an alkyl group are excluded; or a pharmaceuticallyacceptable acid addition salt thereof.
 2. A pyrrolo[2,3-d]pyrimidinederivative or a pharmaceutically acceptable acid addition salt thereofin accordance with claim 1, wherein R¹, R², R³, R⁴, R⁵, Y and Z are asdefined above,with a proviso that R² and R³ do not represent a hydrogenatom at the same time, and that when R¹ represents a hydrogen atom, thecombinations wherein one of R² and R³ represents a hydrogen atom andanother represents an alkyl group are excluded, and that when Y is--N(G)--, G represents a hydrogen atom, the case wherein Z represents ahydrogen atom is excluded.
 3. A pyrrolo[2,3-d]pyrimidine derivative or apharmaceutically acceptable acid addition salt thereof in accordancewith claim 1, wherein R¹, R², R³, R⁴, R⁵, Y and Z are as definedabove,with a proviso that R² and R³ do not represent a hydrogen atom atthe same time, and that when R¹ represents a hydrogen atom, thecombinations wherein one of R² and R³ represents a hydrogen atom andanother represents an alkyl group are excluded, and that when Y islinking group --N(G)--, the case wherein R¹ represents an arylalkyl isexcluded.
 4. A pyrrolo[2,3-d]primidine derivative or a pharmaceuticallyacceptable acid addition salt thereof in accordance with claim 1,wherein Y is a linking group having the formula: ##STR220##
 5. Apyrrolo[2,3-d]pyrimidine derivative or a pharmaceutically acceptableacid addition salt thereof in accordance with claim 1, wherein Y is agroup --N(G)--, and G is a hydrogen atom, methyl group or ethyl group.6. A pyrrolo[2,3-d]pyrimidine derivative or a pharmaceuticallyacceptable acid addition salt thereof in accordance with claim 1,wherein R¹ is a lower alkyl group or allyl group.
 7. Apyrrolo[2,3-d]pyrimidine derivative or a pharmaceutically acceptableacid addition salt thereof in accordance with claim 1, wherein R² is ahydrogen atom, R³ is an alkyl group, allyl group or 2-methylallyl group.8. A pyrrolo[2,3-d]pyrimidine derivative or a pharmaceuticallyacceptable acid addition salt thereof in accordance with claim 1,wherein R⁴ and R⁵ are a hydrogen atom.
 9. A pyrrolo[2,3-d]pyrimidinederivative or a pharmaceutically acceptable acid addition salt thereofin accordance with claim 1, wherein R¹ is methyl group or allyl group;R² is a hydrogen atom; R³ is cyclopropylmethyl group;]allyl group or2-methylallyl group; R⁴ and R⁵ are a hydrogen atom; Y is a linking grouphaving the formula: ##STR221## and Z is a hydrogen atom, alkyl group,alkylcarbonyl group, alkyloxycarbonyl group or alkylcarbonyloxy group;or Y is a linking group having the formula: ##STR222## and Z is an alkylgroup, or an unsubstituted or substituted arylalkyl group; or Y is alinking group having the formula: --N(G)--, G is a hydrogen atom oralkyl group, and Z is an allyl group, arylalkyl group, orheteroarylalkyl group which may be substituted by one to three methylgroups on the alkyl chain; or Y and Z taken together is a morpholinogroup.
 10. A pyrrolo[2,3-d]pyrimidine derivative or a pharmaceuticallyacceptable acid addition salt thereof in accordance with claim 1,wherein R¹ is a methyl group or allyl group; R² is a hydrogen atom; R³is a cyclopropyl-methyl group, allyl group or 2-methylallyl group; Y isa linking group having the formula: ##STR223## and Z is a hydrogen atom;or Y is a linking group having the formula: ##STR224## and Z is ahydrogen atom, isopropyloxycarbonyl group or acetyloxy group; or Y is alinking group having the formula: ##STR225## and Z is a methyl group orbis(4-fluorophenyl)methyl group; or Y is a linking group having theformula: --NH--, and Z is an allyl group, benzyl group, 1-phenylethylgroup, 1-methyl-1-phenylethyl group, 2-phenylethyl group,1-(1-naphthyl)ethyl group, 1,2,3,4-tetrahydronaphthalene-1-yl group,furfuryl group, 3-(2-furyl)propyl group or 2-thienylmethyl group; or Yis a linking group having the formula:--N(CH₃)--, and Z is methyl group,benzyl group or phenethyl group.
 11. A method for treating hypoxemiacomprising administering an effective amount of apyrrolo[2,3-d]pyrimidine derivative or a pharmaceutically acceptableacid addition salt thereof in accordance with claim
 1. 12. Apharmaceutical preparation for therapy of hypoxemia, comprising aneffective amount of a pyrrolo[2,3-d]PYRIMIDINE derivative or apharmaceutically acceptable acid addition salt thereof in accordancewith claim 1.